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Vitamin A (Retinol)

Nutrient Names: Vitamin A, retinol.
Synonym: Preformed vitamin A.
Related Substances: Retinal (retinaldehyde); retinoic acid; retinyl esters, such as retinyl acetate, retinyl palmitate, and retinyl propionate; all-trans dehydroretinol, vitamin A2; beta-carotene (provitamin A) and other provitamin A carotenoids: alpha-carotene, cryptoxanthin, lutein, lycopene, zeaxanthin.

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Antacids	Vitamin A coadministration exerts cytoprotective effect and enhances healing of gastric ulcers.	Coadminister.
Anthelmintic drugs / /	Vitamin A deficiencies are also associated with increased risk of parasitic infections. Combining anthelmintic agents with increased vitamin A intake can reduce symptoms of intestinal parasites while supporting epithelial integrity and immune response, especially when combined with increased fat intake.	Coadminister vitamin A and/or beta-carotene supplements/foods with accompanying lipid intake. Follow with improved nutrient intake (quality and quantity) to reduce susceptibility.
Chemotherapy Cytotoxic Agents / /	Chemotherapeutic agents interact with vitamin A in various ways, from adjunctive vitamin A for nutritive support and amelioration of adverse drug effects to cotherapy using retinoids as chemotherapeutic agents. Pattern of interaction varies depending on patient characteristics, form of cancer, and agents involved. Risk of interference with cytotoxic action through antioxidant effects contentious, but evidence inconclusive and likely not uniform for all agents, conditions, or patients.	Coadministration appropriate in some cases. Retinoid use requires close monitoring by experienced clinicians collaborating on integrative strategy, particularly given significant risk of toxicity. Multiple nutrients providing a network effect are preferred when antioxidants deemed appropriate.
Cholestyramine, colestipol Bile acid sequestrants /	By reducing fat absorption, bile acid sequestrants tend to reduce absorption and assimilation of vitamin A and other fat-soluble nutrients. Significant adverse effects on vitamin A absorption appear less likely than for other nutrients, although may depend on agent used, diet and supplemental intake, and patient characteristics. Available research inconclusive and limited by subject population characteristics, duration, and scope; further research warranted.	Concurrent supplementation with multivitamin providing modest levels of A, D, E, and K with folate, carotenoids, and mixed tocopherols can counter potential adverse effects with little risk and minimal expense.
Colchicine	Colchicine may impair vitamin A absorption and can interfere with retinol homeostasis by blocking release of retinol--retinol binding protein (RBP).	Coadminister vitamin A, beta-carotene, and other potentially affected nutrients.
Corticosteroids, oral / /	Exogenous steroid administration may cause transient increases in levels vitamin A and retinol-binding protein (RBP), whereas extended use may reduce levels of vitamin A and metabolites in plasma and tissues. Concomitant use may enhance drug efficacy by mobilizing hepatic stores and elevating plasma concentrations, particularly in very-low-birth-weight (VLBW) neonates with bronchopulmonary dysplasia. Further research into protective and synergistic effects of coadministration warranted.	Supplement during and after extended steroid administration. Monitor vitamin A and RBP levels.
HMG-CoA reductase inhibitors (statins)	Statin therapy may elevate serum retinol levels, possibly by altering liver function; clinical implications unclear and research preliminary. Clinical trials warranted.	Caution advised with retinol intake during statin therapy. Monitoring (or alternatives to statins) appropriate with compromised liver function.
Medroxyprogesterone / / / / / /	Medroxyprogesterone, as injectable contraceptive or oral hormone replacement therapy (HRT), may elevate serum retinol levels, possibly RBP. Clinical significance, with possible underlying alteration in vitamin A function, is unclear, but serum carotenoids may decrease because of competition and altering vitamin A transport. Response likely to depend on multiple factors, including diet and patient characteristics. Further research warranted.	Conservative practice suggests avoiding retinol administration at high doses unless otherwise indicated. Carotenoid support may be indicated. Monitor with compromised liver function.
Methyltestosterone /	Single case report indicates that methyltestosterone may impair visual function by altering serum levels and metabolism of vitamin A and beta-carotene. This minimal evidence may represent an atypical pharmacogenomic response but suggests the need for further investigation, including potential benefit of nutrient supplementation.	Discontinuation of drug therapy indicated on appearance of adverse effects.
Mineral oil /	Mineral oil may interfere with or otherwise alter absorption of many nutrients, especially with simultaneous intake and extended use. Mixed evidence suggests that impact on various nutrients may vary, possibly elevating serum retinol levels and decreasing beta-carotene levels. Further research warranted; timing, dosage, duration, diet, and other factors likely influence clinical significance.	Separate intake of mineral oil from meals, and supplement administration. Avoid extended use of mineral oil internally.
Neomycin	Oral neomycin, particularly high doses over extended periods, may impair vitamin A absorption and could contribute to depletion pattern. Preliminary evidence suggests further research warranted to assess clinical significance.	Coadminister vitamin A and/or beta-carotene with high-dose internal neomycin use of 2 days or longer.
Oral contraceptives (OCs) / /	OCs (exogenous estrogen and progestin formulations) associated with increased serum levels of vitamin A, at least in part due to increased hepatic synthesis of RBP and elevated export of RBP-retinol complex; lower carotenoid levels may result from competition and alterations of vitamin A transport. Clinical implications of this apparent drug effect on nutrient function uncertain, but further research warranted to investigate this emerging pattern of evidence.	Conservative practice suggests avoiding retinol administration at high doses unless otherwise indicated. Carotenoid support may be indicated. Monitor with compromised liver function.
Orlistat	Orlistat may interfere with absorption of vitamin A and other fat-soluble nutrients. Mixed evidence suggests that impact on various nutrients may vary, with findings ranging from no observed effect to depletion despite concurrent supplementation. Further research warranted; timing, dosage, duration, diet, and other factors likely influence clinical significance.	Concurrent supplementation with multivitamin providing modest levels of vitamins A, D, E, and K with carotenoids and mixed tocopherols may counter possible depletion pattern with little risk and minimal expense.
Retinoids	Concomitant use of supplemental vitamin A and pharmaceutical retinoids not formally investigated, and evidence of clinical significance lacking. Nevertheless, “consensus” considers additive effect inevitable and inherently risky. This conclusion may be reasonable, but clinical trials providing conclusive findings are unlikely.	Avoid supplementation of more than 5000 IU vitamin A during retinoid therapy.
Tetracycline antibiotics /	Concurrent use of vitamin A/retinoids and tetracycline antibiotics associated with severe adverse effects, particularly headaches and pseudotumor cerebri (benign intracranial hypertension). Consensus exists on clinical significance of risk of interaction and contraindication against concurrent use. Effects may be sudden and severe.	Avoid concomitant retinoids, including vitamin A at doses above 10,000 IU/day, during antibiotic therapy employing tetracyclines. Discontinue use immediately if symptoms appear.
Note: See also Beta-Carotene monograph.

nutrient description

This monograph reviews interactions issues relating to and deriving from intake of retinol and other forms of preformed vitamin A and the metabolic processes of these substances within physiological/healthy, dysfunctional, and pathological processes and states. The monograph for beta-carotene focuses on interactions issues involving intake, assimilation, and metabolic processes that constitute provitamin A activity and affect retinol and its metabolic activity. Interactions with some pharmaceutical agents inherently involve both substances and their respective class of related substances.

Chemistry and Forms

Vitamin A is a generic term used to describe the class of compounds that exhibit the biological activity of retinol. The two main sources of vitamin A in foods are retinol and the provitamin A carotenoids. Retinol (an alcohol), retinal (an aldehyde), and retinoic acid are collectively known as “retinoids”; they naturally occur only in animal products and can be classified as “preformed vitamin A.” Some structurally related synthetic analogs (e.g., tretinoin) are also considered retinoids and may exhibit significant, partial, or no retinol-like activity.

Carotenoids are a class of related compounds found exclusively in plants (fruits, vegetables, algae, phytoplankton) and animals that feed directly on high-carotenoid plant sources, such as krill, small saltwater and freshwater crustaceans that accumulate astaxanthin from phytoplankton. Approximately 600 carotenoids have been identified thus far. Beta-carotene, alpha-carotene, lutein, lycopene, cryptoxanthin, and zeaxanthin are principal among those specifically classified as “provitamin A carotenoids”; they are so named because humans can metabolically convert them into retinol. Bonds within beta-carotene are cleaved to form all- trans retinol (and possibly retinal); divergent theories exist regarding the site of this cleavage, the products, and their proportion, although molecular structures suggest that one molecule of beta-carotene would result in two molecules of retinol. It is unreasonable, however, to equate the predicted retinol yields of the various provitamin A carotenoids, then add these to provide units of “vitamin A equivalents,” because in non–vitamin A–deficient humans, only a small proportion of provitamin A carotenoids are actually converted to retinol or retinal.

The dietary supplement labeling convention of stating provitamin A carotenoid content in units of “retinol equivalents” (REs) or international units (IUs) of vitamin A activity has led to a widespread misperception among the lay public and many medical professionals alike, that such supplements contain potentially toxic levels of vitamin A. Potential toxicity of carotenoids such as synthetic beta-carotene in smokers is another issue, unique to beta-carotene, and unrelated to issues of vitamin A toxicity (see section on beta-carotene and other provitamin A carotenoids).

Physiology and Function

In 1913, vitamin A was the first vitamin to be isolated, thus the nomenclature “A”. Researchers initially focused on its key role in vision, particularly in preventing night blindness and xerophthalmia. In 1929, Moore demonstrated that beta-carotene was converted to vitamin A, and 2 years later the chemical structures of both vitamin A and beta-carotene were determined.

Vitamin A is readily absorbed in the duodenum and jejunum in the presence of gastric secretions, bile salts, pancreatic and intestinal lipase, protein, and dietary fat. More than 90% of all dietary retinol is in the form of esters, usually retinyl palmitate. These esters must be hydrolyzed in the intestinal lumen by pancreatic enzymes and within the brush border of the intestinal epithelial cells before absorption. Retinol can be absorbed from a micelle in the presence of bile salts or a nonionic detergent. Retinol is absorbed by diffusion when present in high doses, but at low doses its transport across intestinal epithelial cells is mediated by cellular retinol-binding protein (RBP). In average doses, retinol is almost entirely absorbed, with peak concentrations in 4 hours. Retinol is absorbed two to five times more efficiently than beta-carotene, the bioavailability and absorption of which are also influenced by multiple factors, including the amount of carotenoid in the diet, interactions with other carotenoids, dietary fat and fiber, nutritional deficiencies of zinc and protein, and other disease states.

Excess retinol is converted to retinyl esters again and stored in the liver. Retinol binds to RBP, which serves as the carrier associated with vitamin A transport in the blood. When the amount of vitamin A exceeds the capacity of RBP to bind to it, the excess retinol binds to lipoproteins, and in this form it has toxic effects. The liver holds 90% (or more) of the body's vitamin A stores, which typically approximate 2 years’ requirement for an adult; consequently, it generally does not need to be consumed daily. The lungs and kidneys also store retinol in small amounts. Retinol in storage has a half-life of 50 to 100 days. Vitamin A is present in breast milk. Vitamin A metabolites are eliminated in the bile and urine. When large amounts of retinol are ingested, a portion can be excreted in the feces, independent of biliary absorption and excretion.

Vitamin A is a key micronutrient needed to combat infection and maintain immunity and epithelial cell differentiation and turnover. Retinol and retinoic acid are necessary for maintenance of the structural and functional integrity of epithelial tissue and the immune system, cellular differentiation and proliferation, bone growth, gonadal (testicular and ovarian) function, and embryonic development. Vitamin A also acts as a cofactor in numerous biochemical reactions. A single effect or mechanism cannot account for the diverse vitamin A actions on the immune system.

Retinal is essential for the normal function of the retina, particularly visual adaptation to darkness. Both retinyl esters and beta-carotene from the diet are converted to retinal (11- cis isomer). Retinal is combined with the protein opsin to form rhodopsin in the rods of the retina and iodopsin in the cones. Light hitting the retina causes visual excitation and changes the cis configuration into the all- trans form of retinaldehyde. The rods are particularly sensitive to vitamin A deficiency. When in low supply, the all- trans form generated during the light reaction cannot be converted back to the active rhodopsin. Retinal can be also converted to retinoic acid, the form of vitamin A most directly involved in gene transcription. Approximately 20% to 35% of the retinol in food sources (e.g., cod and other fish liver oils) is in the cis configuration, whereas virtually all the vitamin A in supplements and vitamin A–fortified foods (e.g., dairy products) is in the all- trans configuration. Some evidence suggests that the cis configuration may be essential to certain visual and brain functions, at least in certain individuals.

A small amount of beta-carotene is converted into vitamin A in the body, but beta-carotene and the other carotenoids act independently from vitamin A as antioxidants. Only 30% to 50% of the more than 600 known carotenoids are thought to be converted into vitamin A by the body, with alpha-carotene, beta-carotene, and cryptoxanthin the most widely distributed of the provitamin A carotenoids.

nutrient in clinical practice

Known or Potential Therapeutic Uses

In conventional practice, supplemental vitamin A is generally thought to have no established therapeutic uses other than correcting frank deficiencies. The evidence for efficacy from administration of exogenous vitamin A (as retinol) is often considered “mixed” and “preliminary.” However, both natural and synthetic retinoids have been used as pharmacological agents to treat dermatological disorders, with their action most likely deriving from their effect on the transcription of skin growth factors and their receptors. Acitretin (and previously etretinate) has been employed in the treatment of psoriasis, and tretinoin (Retin-A) and isotretinoin (Accutane) are typically used to treat severe cases of acne vulgaris; tretinoin is also used cosmetically to reduce signs of skin aging. Most oncology uses of retinoids involve retinoic acid, including 13- cis , 9- cis , and all- trans forms.

Historical/Ethnomedicine Precedent

Vitamin A (retinol) is not used historically as an isolated nutrient.

Possible Uses

Acne vulgaris, acute promyelocytic leukemia, alcohol withdrawal support, Alzheimer's disease, anemia (associated with deficiency), autism ( cis-containing fish liver–derived form only), blepharitis, breast cancer, bronchitis, burns, cataracts, celiac disease, cervical dysplasia, childhood diseases, colorectal cancer, conjunctivitis, Crohn's disease (associated with deficiency), cystic fibrosis, diabetes mellitus, diabetic retinopathy (in combination with selenium, vitamins C and E), diarrhea, diverticulitis, eczema, fibrocystic breast disease, food poisoning, gastritis, glaucoma, goiter, hemorrhoids, human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) support, hypothyroidism, ichthyosis (noninflammatory skin peeling), immune function, intestinal parasites, iron deficiency anemia (with iron), keratosis follicularis (Darier's disease), leukoplakia, lichen planus pigmentosus, lung cancer, menorrhagia, mucopolysaccharidosis (Hurler syndrome), myocardial infarction, myeloproliferative disorders, night blindness (nyctalopia), osteoarthritis, osteoporosis, peptic ulcer, peritonitis, pityriasis rubra pilaris, premenstrual syndrome, psoriasis, respiratory syncytial virus (RSV), retinitis pigmentosa, retinopathy (in combination with selenium, vitamins C and E), rosacea, roundworms, rubeola (measles, severe cases, with deficiency, especially to reduce measles mortality in developing countries), seborrhea, sickle cell anemia, skin cancer, sprains and strains (associated with deficiency), surgery (preparation and recovery), tuberculosis, ulcerative colitis, urinary tract infection, varicella (chickenpox), vaginitis, warts, wound healing, xerophthalmia (classic manifestation of vitamin A deficiency).

Vitamin A deficiency is widespread, in association with general malnutrition, in developing countries, particularly among young children. Frank deficiencies are generally considered uncommon in developed countries, especially in adults, but marginal intake and deficiency status are known to occur with inadequate and poor-quality diet, especially in children and elderly persons. Furthermore, individuals who restrict their dietary intake of liver, dairy products, and vegetables rich in beta-carotene increase their risk of developing vitamin A deficiency. Chronic consumption of alcohol can deplete liver stores of vitamin A, which can be further complicated by alcohol-induced liver damage. Chronic consumption of alcohol and acetaminophen can greatly increase the hepatotoxicity of vitamin A supplements (but not of provitamin A carotenoid supplements).

Special Populations

Extremely low-birth-weight infants (≤1 kg [2.2 lb]) are at high risk of a deficiency at birth. Individuals with vitamin A deficiency caused by abnormal storage and transport conditions, including abetalipoproteinemia, diabetes mellitus, fever, hyperthyroidism, cystic fibrosis (with liver involvement), liver disease, and protein deficiency.

Deficiency Symptoms

Blindness, defective tooth and bone formation, diarrhea, diminished immune function, dry skin, increased susceptibility to respiratory and urinary tract infections, loss of appetite, metaplasia and keratinization of respiratory tract cells and other systems/organs, night blindness (nyctalopia), papular eruptions, reduced synthesis of steroid hormones, visual impairment, xerophthalmia.

Dietary Sources

Free retinol is not generally found in foods.

The richest readily available dietary source of vitamin A is fish liver oil, especially cod liver oil. In particular, all- trans dehydroretinol, previously known as vitamin A2, is a vitamin A–related compound found in freshwater fish flesh and liver and, to a lesser extent, in some marine fish; it is estimated to have 40% to 50% of the vitamin A activity of all- trans retinol. Likewise, cis isomers of retinol, exhibiting up to 75% relative activity of all- trans retinol, can account for up to 35% of preformed vitamin A measured in fish liver oils. Oily fish such as herring, pilchards, tuna, and sardines are considered rich sources. Retinyl palmitate , a precursor and storage form of retinol, is found in foods from animal sources and is, along with the acetate ester, the most common form in dietary supplements. Good food sources of vitamin A include liver, kidney, butter, egg yolk, whole milk and cream, whole-milk yogurt, and fortified skim milk. Cod liver oil and halibut fish oil contain high levels of vitamin A and have been used therapeutically.

Carotenoid sources are reviewed in the Beta-carotene monograph.

Nutrient Preparations Available

Many supplements provide a combination of retinol and beta-carotene. Some individuals appear to be able to absorb water-soluble forms of vitamin A supplements better than fat-soluble vitamin A, particularly those with compromised biliary function.

Dosage Forms Available

Capsule, liquid, tablet.

Source Materials for Nutrient Preparations

The primary forms of preformed vitamin A (retinol) in supplements are the vitamin A esters retinyl palmitate and retinyl acetate. Vitamin A can be produced by extraction from fish liver oil, although the more common process is synthesis from beta-ionone.

Dosage Range

One international unit (1 IU) of beta-carotene is equivalent to 1 IU of vitamin A; 1 mg (1000 micrograms [µg]) of beta-carotene is equivalent to 500 µg of vitamin A.

Nutrient values of preformed vitamin A and provitamin A carotenoids are often combined into a single numerical value designating functional vitamin A activity. Originally, the internationally accepted values were international units, with 1 IU being defined as 0.30 µg of all- trans retinol, or 0.60 µg of all- trans beta-carotene. Although the system of retinol equivalents has become the accepted standard, these earlier are still found in many food composition tables and scientific publications.

Strong evidence for lower bioavailability of beta-carotene than previous estimates led to revision of the values for the biological activity of various forms of vitamin A and carotenoids. On the basis of rodent studies, the other provitamin A carotenoids have an estimated 50% of the growth-promoting activity of beta-carotene. Although further research has revealed greater diversity in bioavailability, absorption, and differential biological activity, the initial proportional estimates resulted in units of expression for vitamin A activity called retinol equivalents (REs). Retinol equivalents are now used as the internationally accepted units for vitamin A activity and can be summarized as follows: 1000 REs =1 mg all-trans retinol =6 mg all-trans beta-carotene =12 mg other provitamin A carotenoids =3330 IU vitamin A (retinol) =10,000 IU carotene

However, differences in equivalency when converting beta-carotene to retinol has produced persistent confusion between IU and RE. Calculating total vitamin A activity using the RE system reduces the contribution of provitamin A compared with the IU system. The resultant formula for interconversion follows: RE=IU retionol/3 .33 + IU beta-carotene/10 .0 =µg retinol =µg beta-carotene/6 + µg other provitamin A carotenoids/12

Continued uncertainty about the meaning of bioavailability of carotenoids, shortcomings in methods for determining bioavailability and absorption, and emerging knowledge of numerous factors in individual variability reveal fundamental inadequacies and inaccuracy in current systems for evaluating and comparing various forms of vitamin A, particularly those from dietary intake of carotenoid-containing foods. Given the wide range of reported conversion ratios of beta-carotene to vitamin A in humans, including the ratio of 6:1 for beta-carotene and 12:1 for alpha-carotene and cryptoxanthin devised by the World Health Organization (WHO), it appears prudent to consider all such approaches as, at best, providing only an average estimate that is not applicable to all diets or individuals. Furthermore, isomerization remains a largely unaddressed issue in quantifying provitamin A activity in processed forms of plant products.

Adult

Dietary: 2333 IU/day for women and 3000 IU/day for men, from dietary sources of both vitamin A and beta-carotene, will generally be adequate to support normal gene expression, immune function, and vision. Breast-feeding women: 4000 to 4333 IU (1200-1300 µg) daily.

Supplemental/Maintenance: 2500 IU of vitamin A as retinol, or 5000 IU of vitamin A, total, with at least 50% in the form of beta-carotene.

Pharmacological/Therapeutic: 25,000 IU (7500 µg) of vitamin A daily is typically used. Doses of 100,000 to 400,000 IU/day have been used for limited periods in the treatment of certain conditions with professional supervision. A maximum of 15,000 IU/day may be more appropriate for individuals over age 65 and those with liver disease outside the context of professional supervision.

Toxic: Doses greater than 50,000 IU/day have resulted in toxicity. Adverse effects may occur in adults at intake levels above 25,000 IU (7500 µg) daily, with higher levels, at or above 100,000 IU/day, more likely to result in cumulative toxicity. Pregnant women (or those who could become pregnant during or shortly after extended supplementation) should not exceed 10,000 IU (3000 µg) daily because of the risk of birth defects, less if foods fortified with vitamin A are consumed to a significant degree with any regularity.

Pediatric (<18 years)

Dietary and Supplemental (combined):

Infants, birth to 6 months: 1333 IU (400 µg), or retinol equivalent (RE) (AI, adequate intake).
Infants 7 to 12 months: 1667 IU (500 µg), or retinol equivalent (RE) (AI)
Children, 1 to 3 years: 1000 IU (300 µg)/day (AI)
Children, 4 to 8 years: 1333 IU (400 µg)/day (RDA)
Children, 9 to 13 years: 2000 IU (600 µg)/day (RDA)
Adolescents, females, 14 to 18 years: 2333 IU (700 µg)/day
Adolescents, male, 14 to 18 years: 3000 IU (900 µg)/day (RDA)

Note: Supplementation often advised for children 6 months to 5 years of age (unless diet known to provide adequate intake)
Pharmacological/Therapeutic: 10,000 IU or greater daily for a child is considered high-dose therapy
Toxic: 10,000 IU (3000 µg) daily

Laboratory Values

Plasma retinol: levels less than 1.05 mmol/L indicate deficiency.
Note: Plasma retinol levels are maintained at the expense of liver stores of vitamin A. Thus, a decline in plasma retinol levels appears only when vitamin A deficiency is progressed to a severe degree.
Liver vitamin A content (biopsy): Levels less than 0.07 mmol/g indicate deficiency.
Note: Liver biopsy provides an accurate assessment of body stores of vitamin A.

safety profile

Overview

Vitamin A toxicity is relatively rare. Hypervitaminosis A is caused by excessive intake of preformed vitamin A and has never been attributed to consumption of carotenoids. Preformed vitamin A is rapidly absorbed and slowly cleared from the body. The risk of developing hypervitaminosis A is derived from total cumulative vitamin A intake rather than a specific daily dosage level, and dosage levels necessary to induce hypervitaminosis A vary significantly among individuals. Thus, vitamin A toxicity can occur in two forms: acute and chronic; that is, toxicity may result acutely from high-dose exposure over a short time, or chronically from lower intake.

Acute hypervitaminosis A results from ingestion of a very high dose of vitamin A over a brief period. Typical symptoms include bulging fontanels in infants and headache in adults, nausea, vomiting, fever, vertigo, and visual disorientation. Peeling of the skin may also occur. Chronic hypervitaminosis A is more common than the acute form and results from continued ingestion of high doses for months or even years. Symptoms include anorexia, dry itchy skin, alopecia, increased intracranial pressure, fatigue, irritability, somnolence, pronounced craniotabes (congenital cranial osteoporosis) and occipital edema, skin desquamation, fissuring of the lips, pain in the legs and forearms, neurological disturbances, and lethargy. Elevated blood lipids are also common. Furthermore, because vitamin A is fat soluble, excesses tend to accumulate in fatty tissues.

Doses up to 25,000 units (U) per day of vitamin A are generally regarded as safe, although toxicity has been associated with doses as low as 20,000 IU/day. Alleged toxicity at this lower dose has occurred in persons with liver dysfunction caused by drugs, chronic alcohol intake, viral hepatitis, aging, or protein-calorie malnutrition. Most cases of toxicity in nonpregnant females result from more than 200,000 IU/day supplementation for at least 6 to 8 months. Although widely discussed, the teratogenic risks of vitamin A intake appear to occur rarely; however, the teratogenic risk associated with ingestion of the synthetic retinoids (e.g., all- trans and 13- cis retinoic acid) during pregnancy appears to be much higher.

Reports of adverse effects are associated with doses and durations as low as 20,000 IU/day supplementation for 4 to 6 months. However, doses as high as 500,000 to 1 million IU/day over several years have not caused adverse effects in many people.

Nutrient Adverse Effects

General Adverse Effects

Typical symptoms, especially in children, include drowsiness, fatigue, irritability, vomiting, and bulging of the fontanel. In adults, headaches, dry itchy or scaly skin, brittle nails, alopecia, fatigue, anorexia, diarrhea, gingivitis, cheilosis, bone pain, hepatosplenomegaly, abnormal liver function, and visual disturbances have been reported. Severe cases of hypervitaminosis A may result in hemorrhage, liver damage, and coma. ¹

Generally, discontinuation of vitamin A intake causes symptoms to disappear within a few days with no permanent repercussions, although permanent liver injury has been reported.

Findings from several recent prospective studies suggest that long-term intake of preformed vitamin A in excess of 1500 µg (5000 IU) per day are associated with decreased bone mineral density (BMD) and increased risk of osteoporotic fracture in older men and women, particularly a greater risk of hip fractures in women. ^2-6However, because vitamin D deficiency (defined as a serum 25-hydroxyvitamin D level <20 mg/mL) appears to be relatively common in the general population (particularly older age groups), because vitamin A may antagonize the effects of vitamin D, ⁷ and because vitamin D status was not investigated in any of these reports, the role (if any) of vitamin D status in the higher fracture risk associated with higher intakes of vitamin A is unclear.

Adverse Effects Among Specific Populations

Lower dosage levels are generally recommended in elderly individuals because of increased risk of compromised liver function and attendant increased risk of toxicity, as well as potentially elevated risk of osteoporosis. Individuals with liver disease or diabetes may also have diminished ability to release vitamin A stored in the liver and therefore an elevated risk of toxic accumulation. Individuals with a genetic predisposition to hypercholesterolemia may also be more susceptible to toxicity at lower doses.

Pregnancy and Nursing

The greatest concerns about toxicity are the embryotoxic effects that may occur during early pregnancy. Large doses of vitamin A and most of the retinoids can interfere with normal fetal cell development and cause birth defects, although this is usually observed with other retinoids (compounds related to vitamin A, such as retinoic acid), rather than for vitamin A itself. Thus, excessive dietary intake of vitamin A has been associated with birth defects in humans in fewer than 20 reported cases over the past 30 years. ^8,9Other studies combining human and animal data suggest that up to 30,000 U/day is safe in pregnancy. ¹⁰ Nevertheless, until more conclusive, large-scale data are available, most experts suggest limiting vitamin A intake from food and supplements combined to 10,000 U during pregnancy. This standard recommendation of a 10,000 IU safe limit became institutionalized after the 1995 New England Journal of Medicine report on vitamin A–related teratogenicity. ¹¹

However, a subsequent report by Mastroiacovo et al. ¹² observed only three major malformations among several hundred women exposed to 10,000 to 300,000 IU (median exposure of 50,000 IU) per day, a typical rate of occurrence regardless of vitamin A intake. Furthermore, congenital malformations were lacking in any of the 120 infants exposed to maternal intakes of vitamin A greater than 50,000 IU/day, and this high-exposure group actually demonstrated a 50% decreased risk for malformations, compared with infants not exposed to vitamin A, and a risk level lower than those exposed to midlevel doses (10,000-40,000 IU/day). ¹² Other research has found a beneficial effect of vitamin A supplements in reducing free-radical–induced lipid peroxidation associated with third-trimester pregnancy–induced hypertension, ¹³ thus demonstrating this vitamin's antioxidant activity in an important clinical situation.

In a randomized clinical trial, Fawzi et al. ¹⁴ found that a multivitamin supplement reduced death and prolonged HIV-free survival significantly among children born to women with low maternal immunological or nutritional status. Vitamin A alone, however, was associated with increased risk of HIV transmission from mother to child while nursing. Further research is inappropriate, but prudence advises limited use of vitamin A by HIV-infected women who are nursing or susceptible to pregnancy.

Contraindications

Retinol is contraindicated in patients with compromised liver, hepatitis, or any liver disease. High alcohol intake can induce vitamin A deficiency, but ethanol and retinol may interact to increase oxidative stress and the risk of hepatotoxicity. ¹⁵

Precautions and Warnings

High doses (>10,000 IU/day) of supplemental retinol are contraindicated in women who are or might become pregnant. This upper level may be reduced to 1500 µg (5000 IU) of vitamin A per day if foods fortified with preformed vitamin A constitute a significant component of their diet.

High doses should not be administered to older men and women, especially those with decreased BMD and corresponding increased risk of osteoporotic fractures.

At high dosage levels, especially outside the context of broad-based antioxidant nutrient networks, both vitamin A and synthetic beta-carotene have the potential to elevate triglycerides and increase oxidative stress and thereby increase risk of death from heart disease, particularly in smokers. Supplementation with synthetic all- trans beta-carotene has also been associated with an increased risk of lung cancer in smokers. Notably, however, retinoid therapy in former smokers, using 9- cis-retinoic acid, reverses loss of retinoic acid receptor-beta expression in the bronchial epithelium and may help prevent lung cancer. ¹⁶

interactions review

Strategic Considerations

Vitamin A is generally used in supporting healthy function and treating disorders of the tissues for which it has the greatest affinity: eyes and vision, skin and mucous membranes, cell regeneration and immune function. Both animal and plant foods can serve as dietary sources of vitamin A, but only the preformed vitamin A (primarily retinyl esters and retinol) can contribute to toxicity from excessive dietary intake.

As a nutritional supplement or as a pharmaceutical agent, retinol is primarily administered for its pharmacological activity and not as an antioxidant, as might be a primary intended function of beta-carotene and other carotenoids. In general, retinoids, whether synthetic or natural in origin, should be considered as prescription drugs because their typical use in high doses will usually override normal physiological regulatory mechanisms, thus introducing the risk of accumulation, toxicity, and adverse effects. Apart from application in supporting development and immune function in infants and children, vitamin A has largely been displaced by synthetic retinoids in conventional practice.

Vitamin A continues to play a limited role in oncology therapeutics. In some cases, particularly involving squamous tumors, up to 1 million units/day emulsified vitamin A (the preferred form because of lower hepatic accumulation) is administered daily until significant cheilosis develops, then lowered to 100,000 IU/day and gradually increased again. With such use, experienced physicians follow the blood retinol level, pushing it to the upper limit of normal, and take care to monitor hepatic enzymes, symptoms, and skeletal metabolism and adjust as needed to prevent bone loss. It is important to remain aware that liver damage may result from long-term use of 25,000 IU nonemulsified A, especially in conjunction with chemotherapeutic agents such as tamoxifen. Within conventional oncology practice, all- trans retinoic acid (ATRA), combined with chemotherapy, has become standard treatment for promyelocytic leukemia over the past 10 years. In contrast to such uses within conventional pharmacology, retinol and its esters are really the only “nutrient” forms of vitamin A.

nutrient-drug interactions

Antacids

Aluminum carbonate gel (Basajel), aluminum hydroxide (Alternagel, Amphojel); combination drugs: aluminum hydroxide, magnesium carbonate, alginic acid, and sodium bicarbonate (Gaviscon Extra Strength Tablets, Gaviscon Regular Strength Liquid, Gaviscon Extra Strength Liquid); aluminum hydroxide and magnesium hydroxide (Advanced Formula Di-Gel Tablets, co-magaldrox, Di-Gel, Gelusil, Maalox, Maalox Plus, Mylanta, Wingel); aluminum hydroxide, magnesium trisilicate, alginic acid, and sodium bicarbonate (Alenic Alka, Gaviscon Regular Strength Tablets); calcium carbonate (Titralac, Tums); magnesium hydroxide (Phillips’ Milk of Magnesia MOM); combination drugs: magnesium hydroxide and calcium carbonate (Calcium Rich Rolaids); magnesium hydroxide, aluminum hydroxide, calcium carbonate, and simethicone (Tempo Tablets); magnesium trisilicate and aluminum hydroxide (Adcomag trisil, Foamicon); magnesium trisilicate, alginic acid, and sodium bicarbonate (Alenic Alka, Gaviscon Regular Strength Tablets); combination drug: sodium bicarbonate, aspirin, and citric acid (Alka-Seltzer).

Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable
Evidence Base:

Preliminary

Effect and Mechanism of Action

Vitamin A provides nutritive support for tissue regeneration within the context of suppression of irritative gastric secretions by antacids.

Research

Patty et al. ¹⁷ investigated the combined effects of vitamin A and antacids on ulcer healing in a multiclinical, multicenter, randomized, prospective trial involving 60 patients with chronic gastric ulcer divided into three groups; they also studied the basal and maximal gastric secretory responses of 12 patients. For 4 weeks, subjects in the first group were treated with antacids only, in the second group with antacids plus vitamin A (50,000 IU orally three times daily), and in the third group the combination of antacids, vitamin A, and cyproheptadine (4 mg orally three times daily). Endoscopic analysis and planimetric measurement of ulcer sizes revealed a significant pattern of enhanced healing associated with concomitant use of vitamin A. Gastric ulcers were completely healed in 15 of 40 individuals who received vitamin A. The reduction in ulcer size was greater in the group receiving vitamin A plus antacids after both 2 and 4 weeks of use. Furthermore, vitamin A (given in doses of 100,000 IU intramuscularly) decreased neither basal nor maximal gastric secretory responses. These findings demonstrate a cytoprotective effect of vitamin A and suggest that coadministration with vitamin A and antacids may be more effective than antacids alone in healing ulcers.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Patients with gastric ulcers being treated with antacid medications may derive enhanced clinical outcomes through coadministration of vitamin A. Further research is warranted to determine safe and effective dosage levels, define parameters for establishing appropriate treatment period, and shape clinical guidelines for phased withdrawal of antacids on resolution of ulcerations. Concomitant administration of nutrients adversely affected by suppression of gastric acidity, such as vitamin B ¹² , folic acid, beta-carotene, and vitamin D, may also be warranted depending on the actions of the particular agent used, duration of use, and patient characteristics. It is not known whether similar synergy might exist between vitamin A and H ² blockers and/or proton pump inhibitors. The relationship between vitamin A supplementation and Helicobacter pyloriinfection has also not yet been systematically investigated.

Anthelmintic Drugs

Albendazole (Zentel), levamisole (Ergamisol), praziquantel (Biltricide).

Beneficial or Supportive Interaction, Not Requiring Professional Management

Probability: 2. Probable
Evidence Base:

Consensus

Effect and Mechanism of Action

Helminth infections, particularly roundworms, can interfere with vitamin A absorption, partly through their effect on intestinal epithelial cells, thus depleting body stores of vitamin A. Vitamin A deficiencies are also associated with increased risk of parasitic infections. Increased intake of vitamin A sources, whether through diet or supplementation, can counter this adverse effect of intestinal parasites and can be further enhanced by coadministration of anthelmintic agents. Enhanced vitamin A status may then help prevent or reduce symptoms associated with intestinal worms, especially roundworm. Furthermore, vitamin A supplementation has often been suggested for its physiological role in maintaining epithelial integrity, its ability to stimulate specific and nonspecific immune functions, and its beneficial effects on diarrhea. Absorption of vitamin A can also be supported by increasing levels of dietary fat intake, because both retinoids and beta-carotene are fat soluble.

Research

Depressed iron status and serum retinol have been associated with infections involving intestinal helminths, particularly Ascaris lumbricoidesand hookworm, in South Asian and African children. ¹⁸ Deworming can contribute significantly to the prevention of morbidity and mortality associated with vitamin A deficiency among children in rural communities where intestinal helminth infection is prevalent. ¹⁹

Jalal et al. ²⁰ studied the effect of food sources of beta-carotene, increased dietary fat, and A. lumbricoidesinfection on serum retinol concentrations in children, 3 to 6 years of age, in Sumatra, Indonesia. Some children were administered levamisole for deworming before the feeding period; others were untreated and remained infected. Incorporation of beta-carotene sources (primarily as red sweet potatoes) into the diet significantly increased serum retinol concentrations, to the greatest degree when meals contained both additional beta-carotene sources and extra fat and the children had been dewormed. Adding more fat to the meal and deworming the children caused a rise in serum retinol similar to that observed when the diet included additional beta-carotene. Furthermore, the combined effects of fat and deworming were additive to the effects of additional beta-carotene sources. When the meal contained additional beta-carotene sources, added fat further improved serum retinol concentrations, but only with low-grade A. lumbricoidesinfection.

In a study involving 977 Kenyan children, Mwaniki et al. ²¹ found that the combination of multi-micronutrient supplementation, including 1000 µg (3300 IU) vitamin A, and multihelminth chemotherapy, using albendazole and praziquantel, reduced egg output of Schistosoma mansoni, a species of trematode blood flukes, and increased serum retinol, regardless of initial serum retinol.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Increasing vitamin A or beta-carotene intake through beta-carotene–rich dietary sources and administration of supplements, especially with additional dietary fat intake, can reduce susceptibility to and adverse outcomes from intestinal helminth infections and work synergistically with anthelmintics to eradicate such infections. Health care professionals treating such infections or supporting preventive measures in at-risk populations can improve clinical outcomes by increasing dietary sources of vitamin A, through plant foods rich in beta-carotene and other nutrients, or through administration of broad-based nutritional supplements. Dosing levels for supplements would be based on intake needs and safety restrictions, as determined by age, weight, and other relevant factors.

Chemotherapy (Cytotoxic Agents)

Evidence: Cisplatin ( cis-diaminedichloroplatinum, CDDP; Platinol, Platinol-AQ), cyclophosphamide (Cytoxan, Endoxana, Neosar, Procytox), docetaxel (Taxotere), fluorouracil (5-FU; Adrucil, Efudex, Efudix, Fluoroplex), methotrexate (Folex, Maxtrex, Rheumatrex), paclitaxel (Paxene, Taxol), tamoxifen (Nolvadex).

Effect and Mechanism of Action

Vitamin A has been used concurrently with chemotherapy or other forms of oncological care in many ways, and the patterns of interaction involved are not characterized by a singular or consistent mechanism of action or therapeutic strategy. All forms of cytotoxic chemotherapy are fundamentally aimed at killing dividing cells, but each class of agents clearly has different modes of action. For example, cyclophosphamide (Cytoxan) is an alkylating agent, 5-FU is an antimetabolite, and taxanes are mitosis disruptors that bind the mitotic spindle structures. Vitamin A (as retinol or retinyl esters) has its own antioxidant activity, although it is generally considered not as potent as that of the provitamin A carotenoids, which have a larger electron cloud of conjugated double bonds to utilize. In oncology, however, retinol/retinoid activities more likely are related to cell signaling (through retinoid-responsive elements of nuclear DNA), which involves cellular/tissue differentiation and induction of apoptosis.

Vitamin A with Chemotherapy in Treatment of Late-Stage Breast Cancer

An additive or synergistic effect has been reported and is presumed to be the underlying effect of concomitant use.

Antioxidants and Chemotherapy

Oxygen radicals have increasingly come under investigation as highly toxic stressors contributing to the causes of many diseases, including many forms of cancer. Vitamin A is among the nutrients well known as antioxidant agents. Antioxidants protect the body against cellular oxidative damage and thus some of the adverse effects induced by cisplatin and other cytotoxic drugs. Many nutritionally oriented health care professionals consider the oxidative damage caused by chemotherapy to be a particularly troublesome adverse effect given that evidence increasingly points to oxidative damage as a contributing factor in the causation of many cancers. However, many oncologists reason that antioxidants might be contraindicated with some agents or during some phases of chemotherapy because many chemotherapeutic agents attack cancer cells by inducing oxidative damage. For example, activation of cyclophosphamide requires hepatic oxidation, a process with which antioxidant nutrients could theoretically interfere. However, no substantial clinical research in humans has yet emerged to support this speculation or to warrant considering antioxidants as inherently contraindicated during chemotherapy.

Research

Sacks et al. ²² have conducted a number of experiments into the effects of retinoids on cancer cells, directly and in conjunction with chemotherapeutic agents. In 1990 they demonstrated that beta-ATRA inhibits macrocellular growth of a multicellular tumor spheroid model for squamous carcinoma, but allows for continuing DNA synthesis and cell cycle progression, with these two effects reconciled by a cell death effect. In 1995 these investigators used eight squamous carcinoma cell lines and reported that retinoic acid worked synergistically with chemotherapy to modulate cell growth and proliferation. ²³ Although suggesting the clinical value of vitamin A as a component of integrative oncological therapeutics, such research typically evolves from nutrient administration to cotherapies using retinoids as pharmacological agents.

In a randomized controlled trial involving 100 women with late-stage metastatic breast cancer. Israel et al. ²⁴ found that postmenopausal women experienced enhanced remission rates, duration of response, and projected survival, compared with controls, when administered 350,000 to 500,000 IU of vitamin A daily (according to body weight, given indefinitely) with their chemotherapy. Serum retinol levels were significantly increased only in the subgroup of postmenopausal women given high-dose vitamin A. Premenopausal women did not demonstrate significant elevations of serum retinol levels or significantly improved outcomes from the combined therapy.

The interactions between chemotherapeutic agents and antioxidant nutrients display similar patterns but also diversity in usage, action, and attention by researchers. The issue of antioxidants in oncology remains controversial, with conjecture on both sides and a slowly emerging body of clinically based evidence. In general, clinicians and researchers most familiar with antioxidants consistently emphasize the importance of using antioxidants in clusters capable of creating an antioxidant network, as a means of averting the potential for individual nutrients to act as pro-oxidants under conditions of high oxidative stress, particularly in individuals with multiple biochemical stressors and compromised physiology; higher doses are often recommended as more efficacious than lower doses. Furthermore, high-quality randomized trials that control for the antioxidant contribution of diet, which may well confound the contribution of supplements, have not been performed and this key issue of study design not adequately addressed by those with “conclusive” findings.

Animal research indicates that vitamin A may enhance antitumor effect of 5-fluorouracil. ²⁵

Besides no research linking antioxidant vitamins to reduced cyclophosphamide effectiveness in cancer treatment, Ghosh and Das ²⁶ found that vitamin A supplementation enhancedthe therapeutic action of cyclophosphamide in mice with vitamin A deficiency. Preliminary studies on humans undergoing chemotherapy with cyclophosphamide have indicated promise of increased survival rates when supplemented with antioxidant nutrients, including vitamin A. Nevertheless, although antioxidants might have many benefits as cotherapies, evidence as to their effectiveness in patients taking cyclophosphamide is inconclusive. ^27-30 On the other hand, no conclusive evidence has confirmed concerns of a potential adverse interaction resulting from antioxidant coadministration interfering with activation of cyclophosphamide (since it requires oxidation in the liver) and its effectiveness. ³¹ Thus, such concern remains speculative at this time.

A variety of studies, primarily in vitro and animal, have found vitamins A, C, and E; N-acetylcysteine; and other antioxidants to increase the effectiveness of and reduce adverse effects of chemotherapy in several types of cancer. ^27,32-43 In a review of 71 scientific papers, Prasad et al. ⁴⁴ found no evidence to support the proposition that antioxidants interfere with the therapeutic effect of chemotherapy. To the contrary, the data suggest that such combinations would do more to increase efficacy. The authors express caution, but their review indicates a low risk that these antioxidants prevent the therapeutic activity of chemotherapy, and more likely that antioxidants enhance the action of chemotherapeutic agents. Simone et al. ^45a-b arrived at parallel conclusions in a similar review of 280 peer-reviewed papers. Prasad et al. ^45c conclude the following: Antioxidants such as retinoids, vitamin E, vitamin C and carotenoids inhibit the growth of cancer cells. These antioxidants individually, and in combination, enhance the effects of x-irradiation, chemotherapeutic agents, and certain biological response modifiers such as hyperthermia, sodium butyrate and interferon, on cancer cells. Antioxidants individually protect normal cells against some of the toxicities produced by these therapeutic agents. Therefore, the fear of oncologists and radiation therapists that these antioxidants may protect cancer cells against free radicals that are generated by these agents is unfounded. It should be pointed out that other antioxidants such as sulfhydryl compounds will protect cancer cells at least against radiation damage. This is not true for any of the proposed antioxidant vitamins and carotenoids.

Several researchers have offered the seemingly paradoxical conclusion that the appropriate administration of antioxidant inhibitors and free-radical–generating compounds may be a useful strategy in the treatment of solid tumors. However, reports at the 1999 American Society of Cell Biology annual meeting suggested that vitamin A and E–deficient mice were less susceptible to brain tumor progression than non–vitamin-deficient control animals. Salignik et al. ⁴⁶ suggested that suppression of free radicals by the antioxidant vitamins may suppress apoptosis (programmed cell death). After reviewing the relationship between chemotherapy and antioxidants, Weijl et al. ³⁸ rebuffed warnings to avoid antioxidants during chemotherapy, but also determined that no substantive evidence supported the use of antioxidants to provide relief from the adverse side effects of chemotherapy. Although most preclinical evidence and the limited clinical evidence suggest a greater likelihood of benefit than harm from coadministration of antioxidants with radiotherapy and chemotherapy to treat human cancer, existing evidence is just beginning to answer the question, ^46a and large, well-designed clinical trials are needed for definitive answers. This question is important to public health because most mainstream medical and radiation oncology practitioners routinely proscribe concurrent use of antioxidant supplements, but many cancer patients use them covertly, based on the available information, accessible through the internet and other sources. Diet and antioxidant content vary among cancer patients, which confounds clinical trial design and has not been adequately addressed.

Interactions from coadministration of antioxidants and nutrients other than vitamin A are reviewed in the monographs of those nutrients.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The use of high doses of vitamin A to complement conventional chemotherapy offers significant potential for clinical benefit. The levels of vitamin A administered as part of the French research reviewed are much higher than levels generally considered toxic.

Physicians prescribing chemotherapy for breast cancer may want to discuss with patients the potential therapeutic value of adding vitamin A to their treatment regimen. Close supervision and regular monitoring of serum retinol levels, hepatic enzymes, and symptoms (e.g., cheilosis, headache) are required for proper dosing of vitamin A at high levels and for evaluation of efficacy, potential adverse effects, and the disease process itself.

The use of vitamin A as a chemotherapeutic agent, alone or in combination with conventional chemotherapy, involves potential risks and requires supervision by health care professionals experienced in both conventional pharmacology and nutritional therapeutics, preferably collaborating in a multidisciplinary approach to integrative oncology care. Likewise, practitioners who judiciously use antioxidants during chemotherapy or other conventional cancer care are advised to question patients about self-prescribing of antioxidants. Such concomitant use could be problematic and contraindicated, beneficial and appropriate, or both, for certain patients taking individualized and evolving dosage levels at coordinated intervals and durations. In almost all cases the administration of multiple antioxidants, such as mixed tocopherols, vitamin C, N-acetylcysteine, parenteral glutathione, coenzyme Q10, and proanthocyanadins, is more likely to be appropriate, safe, and effective than single agents in high doses.

High doses of vitamin A carry significant potential risks of toxicity, particularly with extended use. As noted previously, some physicians experienced in nutritional therapeutics and integrative oncology have employed dosage levels of up to 1 million units per day, using emulsified vitamin A for short periods, typically followed by reductions to 100,000 IU/day. Development of significant cheilosis can be used as a physiological monitor for toxicity and the need to reduce dosage levels until it resolves, then consider dose escalation again, based on clinical status and response.

Because the emulsified form of vitamin A is water soluble, it is absorbed directly into the lymphatics of the small intestine, thus obviating the need for micelle formation by bile salts and avoiding immediate processing by the liver (“first pass” metabolism of food components that form micelles and are transported through the portal vein to the liver). This allows larger amounts of vitamin A to reach the peripheral tissues and decreases hepatic accumulation.

Women who could become pregnant should avoid vitamin A doses greater than 10,000 IU (3000 µg) per day because it can be teratogenic, even though typical chemotherapeutic agents present significant risks for causing birth defects, particularly in the first trimester of gestation. Generally, for pharmacological action rather than supplementation support, vitamin A doses up to 25,000 IU (7500 µg) per day are considered safe for postmenopausal women and males. Nevertheless, the risk of liver damage should always be considered when administering retinoids, especially in patients with compromised liver function or chronic infection with hepatitis B or C or who are regularly ingesting hepatic toxins such as alcohol or large doses of acetaminophen. Likewise, it is also important to monitor skeletal metabolism, optimize vitamin D status by monitoring the 25-hydroxyvitamin D blood level, and adjust vitamin A dosage and serum retinol levels as appropriate to prevent bone loss.

Cholestyramine, Colestipol, and Related Bile Acid Sequestrants

Evidence: Cholestyramine (LoCholest, Prevalite, Questran), colestipol (Colestid).

Extrapolated, based on similar properties: Colesevelam (WelChol).

	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management
	Adverse Drug Effect on Nutritional Therapeutics, Strategic Concern

Probability: 3. Possible
Evidence Base:

Emerging and/or

Mixed

Effect and Mechanism of Action

Absorption of dietary (and supplemental) sources of vitamin A requires bile salts and the presence of lipids. Bile acid sequestrants, such as cholestyramine and colestipol, decrease lipid digestion and absorption. In the process, they also reduce absorption of the fat-soluble vitamins (e.g., vitamin A) and other nutrients. ^47-51 Vitamin A (and beta-carotene) may also increase triglyceride levels.

Research

The general consensus over the past 40 years is that drugs that alter fat absorption and bile function will disrupt absorption and assimilation of fat-soluble nutrients. However, the evidence on the degree of such impairment, the nutrients affected, and the clinical significance is mixed, inconclusive, and still emerging. Early research by Longneck and Basu and later by West and Lloyd ⁵² informed several review articles that posited a general impairment of absorption of vitamin A and fat-soluble nutrients by bile acid sequestrants and other antilipidemic agents. Subsequent human trials have investigated the significance of these effects on nutrients for various medications in different patient populations.

West and Lloyd ⁵² (1975) studied the effects of cholestyramine (mean dosage, 0-6 g/kg/day) on 18 children with familial hypercholesterolemia over 1 to 2½ years. In addition to a major reduction in serum folate concentration and red blood cell (RBC) folate, these researchers also noted “a significant decrease in the mean serum concentrations of vitamins A and E and of inorganic phosphorus over the first two years of treatment, although values remain within the normal range.” They concluded that “routine administration of fat-soluble vitamins appears unnecessary but it is prudent to measure prothrombin time [to assess vitamin K status] and serum vitamins A and E at intervals.” ⁵²

In a study of type IIa hyperlipoproteinemic patients, Probstfield et al. ⁵³ observed that serum total carotenoid levels fell by 30% after administration of colestipol (30 g/day) for 6 months, most likely from decreased absorption of carotenoids by bile acid sequestrant administration, but that serum vitamin A levels were not significantly altered.

In 1987, Knodel and Talbert ⁵⁰ reported that “large doses of cholestyramine (>32 g/day) may be associated with malabsorption of fat-soluble vitamins,” but concluded that impaired absorption of vitamins D and K presented the most significant clinical risk with long-term therapy, with bone loss and bleeding disorders being the potential adverse outcomes.

Tonstad et al. ⁵⁴ investigated the effects of colestipol granules (10 g/day) and low-fat diet in an 8-week, double blind, placebo-controlled trial, followed by open treatment for 44 to 52 weeks, on low-density lipoprotein (LDL) cholesterol levels in 37 boys and 29 girls, age 10 to 16 years, with familial hypercholesterolemia. Serum concentrations of vitamins A and D, as well as other relevant nutrient parameters, were not affected significantly in the colestipol group, even though levels of serum folate, vitamin E, and carotenoids were significantly reduced. Thus, although these researchers did not suggest a need for compensatory enhancement of fat-soluble nutrients in general or vitamin A in particular, they did recommended supplementation with folate and “possibly vitamin D.” They also noted the high degree of noncompliance among the adolescents in the study.

This trend toward a significant interaction raises serious questions given the ongoing debate on the correlation between nutrient status, particularly antioxidants, and long-term risk of coronary heart disease. Most importantly, with limited research and no follow-up investigation of long-term effects (i.e., decades) of such drug-induced nutrient depletion patterns on nutrient status, healthy cardiovascular function, and ultimate outcomes, the data are suggestive but inconclusive in regard to benefit versus risk.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Although not always necessary, multivitamin/mineral supplementation with vitamin A and other affected nutrients can provide a safe and inexpensive means of avoiding adverse effects from these medications without interfering with (and perhaps enhancing) the therapeutic goal of supporting healthy cardiovascular function and reducing risk. Vitamin A and other fat-soluble nutrients (as well as folic acid and many medications) should be taken 1 hour before or 4 to 6 hours after bile acid sequestrants for optimal absorption. It may be more effective to coadminister water-miscible vitamin A to patients undergoing long-term bile acid sequestrant therapy. Patient characteristics will influence the need for compensatory nutrient administration, particularly age, typical diet, digestive function, comorbid conditions, and pharmacogenomic response to the medication.

Colchicine

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Probability: 4. Plausible or 2. Probable
Evidence Base:

Preliminary

Effect and Mechanism of Action

Oral colchicine may impair absorption of vitamin A and other nutrients. ^55,56 Colchicine also blocks hepatic release of retinol-RBP and thereby impairs upregulation of serum retinol and interferes with serum retinol homeostasis.

Research

Race et al. ⁵⁵ reported that oral colchicine can induce intestinal malabsorption, affecting beta-carotene and other nutrients.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing colchicine for an extended period can suggest to patients the likely benefit of supplementing with a high-potency multivitamin/mineral supplement to compensate for potential drug-induced depletion of vitamin A, beta-carotene, and other nutrients. Further research through well-designed human trials is warranted to determine the severity, frequency, and clinical implications of this probable interaction and to identify characteristics of individuals most susceptible to clinically significant adverse effects.

Corticosteroids, Oral

Betamethasone (Celestone), cortisone (Cortone), dexamethasone (Decadron), fludrocortisone (Florinef), hydrocortisone (Cortef), methylprednisolone (Medrol) prednisolone (Delta-Cortef, Orapred, Pediapred, Prelone), prednisone (Deltasone, Liquid Pred, Meticorten, Orasone), triamcinolone (Aristocort).

	Prevention or Reduction of Drug Adverse Effect
	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management
	Potential or Theoretical Adverse Interaction of Uncertain Severity

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Extended use of oral corticosteroids can impair immune function and wound healing. The nutritive effect of vitamin A on immune function and tissue regeneration could prevent and support recovery from such adverse drug effects. Evidence indicates that oral corticosteroids may deplete tissue levels of vitamin A. However, some oral steroids may stimulate transient increases in plasma concentrations of vitamin A and RBP in some circumstances.

Research

Hunt et al. ⁵⁷ observed that administration of topical or internal vitamin A reversed the inhibitory effect of cortisone on healing of open wounds and improved wound healing in 8 of 10 patients receiving corticosteroid therapy. Theoretically, concomitant vitamin A supplementation might interfere with the therapeutic action of corticosteroids in some patients, but evidence is lacking. ⁵⁸

Steroidal anti-inflammatory drugs may contribute to depletion of vitamin A. Using adult male rats, Atukorala et al. ⁵⁹ found that the administration of large doses of corticosterone resulted in a rapid loss of vitamin A from the plasma, liver, adrenals, and thymus. Of the organs studied, the thymus appeared to be the most sensitive to treatment. Subsequent coadministration of vitamin A with corticosterone reversed the steroid-mediated depression of vitamin A levels in plasma and tissue. Also using a rat model, Georgieff et al. ⁶⁰ found significant reductions in liver and lung tissue concentrations of vitamin A, retinol, and individual retinyl esters in animals treated with dexamethasone, including those assessed as “vitamin A sufficient” at the onset and demonstrating transient elevations in serum retinol levels in response to the drug.

In a prospective cohort study involving very-low-birth-weight (VLBW) neonates with bronchopulmonary dysplasia (BPD), Shenai et al. ⁶¹ investigated the effects of a 7-day course of dexamethasone to test the hypothesis that vitamin A status is critical for the therapy's beneficial pulmonary response. They measured plasma concentrations of vitamin A and RBP at baseline, then during and after dexamethasone treatment, and graded pulmonary response to dexamethasone daily. A “significant, yet short-term, increase in plasma concentrations of both vitamin A and RBP was observed in most infants treated with dexamethasone.” Also, “plasma vitamin A and RBP responses to dexamethasone tended to be higher in infants with a positive pulmonary response than in those with a negative response. Accounting for gender, a vitamin A response with each 10.0 microg/dL increment in plasma vitamin A concentration was associated with a 60% increase in the odds favoring a positive pulmonary response to dexamethasone.” They attributed the observed increase in plasma concentrations of both vitamin A and RBP to endogenous mobilization of hepatic vitamin A stores and concluded their findings “suggest that the beneficial pulmonary response to dexamethasone in infants with BPD is influenced, at least in part, by the vitamin A status.” ⁶¹ Potential synergy derived from coadministration of vitamin A was not investigated in relation to this research but may warrant investigation, given the evidence that vitamin A and its active metabolites are important to premature infants in general and support healthy respiratory epithelial differentiation and growth in particular.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing oral corticosteroids, especially for extended periods, are advised to consider coadministration of or subsequent supplementation with vitamin A. Daily doses of up to 25,000 IU (7500 µg) of vitamin A are considered safe for men and postmenopausal women for limited periods. However, women who may become pregnant should restrict their daily intake of vitamin A to less than 5000 IU (1500 µg) in supplemental form. Alternatively, when beta-carotene is used as the supplemental source, daily doses of 25,000 IU (15 mg), or even as high as 100,000 IU (60 mg), are considered safe, except in smokers (see Beta-carotene monograph). The temporary elevations of serum levels reported in the literature may not be problematic and may be beneficial in some patients but could be inappropriate for others, especially those with compromised liver function. Whenever administering vitamin A, especially in doses over 50,000 IU/day, it is important to monitor serum levels for inappropriate excess and to advise patients to report headaches or other signs of toxicity promptly. Likewise, with drugs such as steroids, it is equally important to be alert for depleted vitamin A status.

HMG-CoA Reductase Inhibitors (Statins)

Atorvastatin (Lipitor), fluvastatin (Lescol, Lescol XL), lovastatin (Altocor, Altoprev, Mevacor), combination drug: lovastatin and niacin (Advicor), pravastatin (Pravachol), rosuvastatin (Crestor), simvastatin (Zocor); combination drug: simvastatin and extended-release nicotinic acid (Niaspan).

Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

The 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors may increase serum retinol levels. The question of how HMG-CoA reductase inhibition might alter liver regulation of vitamin A has not been investigated.

Research

Muggeo et al. ⁶² observed a pattern of elevation in serum retinol levels over 2 years of therapy in 37 hypercholesterolemic patients treated with diet modification and HMG-CoA reductase inhibitors.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Pending further research with well-designed clinical trials of sufficient size, physicians prescribing HMG-CoA reductase inhibitors should monitor blood levels of vitamin A in patients also taking this nutrient, particularly those with compromised liver function, and consider alternatives to statins in compromised patients. Furthermore, regular monitoring of liver function, especially enzyme levels, is important for prudent management of all patients taking statin drugs. Coadministration of coenzyme Q10 is also appropriate to prevent adverse effects upon endogenous coenzyme Q10 synthesis by HMG-CoA reductase inhibition.

Medroxyprogesterone

Conjugated equine estrogens and medroxyprogesterone (Premelle cycle 5, Prempro); medroxyprogesterone, oral (Cycrin, Provera); Medroxyprogesterone, injection (Depot medroxyprogesterone acetate, DMPA; Depo-Provera, Depo-subQ Provera 104); progestin and estrogen injectable: estradiol cypionate and medroxyprogesterone acetate (Cyclofem, Lunelle). See also Oral Contraceptives below.

	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Bimodal or Variable Interaction, with Professional Management

Probability: 3. Possible or 2. Probable
Evidence Base:

AMPERSANDthinsp;

Emerging

Effect and Mechanism of Action

Medroxyprogesterone acetate (MPA) use is associated with elevations in serum retinol levels. Exogenous estrogen and progestin increase hepatic synthesis of RBP, thus increasing the export of RBP-retinol complex in the blood.

Research

Numerous clinical trials have investigated the effect of medroxyprogesterone administration, whether for contraception or in menopausal hormone replacement therapy (HRT), on blood levels of vitamin A and its metabolites as well as other nutrients. Most studies report increased serum retinol levels, with 40% mean increases in some trials; one study also noted RBP elevations. ^63-67 In 12 nonlactating healthy Thai women, Amatayakul et al. ⁶³ found no significant changes in levels of several nutrients, including vitamin A serum levels, before and with daily coadministration of a vitamin-mineral formulation that included vitamin A and beta-carotene, in association with 1 year of MDA use as an injectable contraceptive (150 mg intramuscularly every 90 days). In a subsequent study on the effect of 1 year of oral contraceptive (OC) use on liver vitamin A storage, as assessed by the relative dose response (RDR) test, these researchers reported that daily (one capsule) or periodic (two capsules 7 days per month) multivitamin supplementation, including 1700 µg vitamin A per capsule, did not significantly influence vitamin A serum values. However, the RDR test after 13 cycles was elevated in one woman who had taken OCs and the periodic multivitamin supplement; it reverted to normal after supplementation with vitamin A. ⁶⁵

Given the inadequate nutritional intake or compromised nutrient status of the women in some of these studies, the researchers have interpreted the phenomena of elevated serum retinol as beneficial. However, in the study of Nigerian women, whose diet is typically high in carotenoids, Wien and Ojo ⁶⁸ reported that serum carotene was lower in OC users (combination estrogen-progestogen) than in groups using intrauterine device (IUD) or injectable progestogen. These researchers concluded that “more detailed study of plasma transport forms of vitamin A is needed to determine if the very high serum vitamin A levels seen in some OC users in this population are potentially harmful.”

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing medroxyprogesterone for contraception or menopausal HRT should consider monitoring blood levels of vitamin A, particularly in patients with compromised liver function. vitamin A supplementation may need to be avoided in some patients; in others it might be indicated, depending on patient characteristics and response to the medication. Enhanced carotenoid intake (diet, supplementation) may be beneficial. Dietary intake of preformed vitamin A and provitamin A carotenoids, nutritional status, age and menstrual status, dose, form, and therapeutic intent all influence how much medroxyprogesterone alters vitamin A levels and function and whether this is beneficial, adverse, or insignificant.

Methyltestosterone

Methyltestosterone (Android, Methitest, Testred, Virilon); combination drug: methyltestosterone and esterified estrogens (Estratest, Estratest HS). Related but evidence lacking for extrapolation: Fluoxymesterone (Halotestin); testolactone (testolacton; HSDB 3255, SQ 9538; Fludestrin, Teolit, Teslac, Teslak); testosterone cypionate.

	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management

Probability: 6. Unkown
Evidence Base:

Inadequate

Effect and Mechanism of Action

The mechanism involved in the following report is not known. ⁶⁹ Also, no research has focused on this potential interaction, its mechanisms, susceptibility factors, or clinical implications.

Report

Nisbett et al. ⁶⁹ reported the case of a 59-year-old man with a 3-month history of night blindness and a 9-month history of steatorrhea subsequent to his initiation of therapy with methyltestosterone. Low serum levels of carotene (0.1 mmol/L) and vitamin A were accompanied by numerous changes in visual function. The symptoms and the biochemical and electrophysiological abnormalities resolved within 9 months of the discontinuation of methyltestosterone.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Although this report may represent an anomalous phenomenon, it still suggests a need for further research. Physicians prescribing methyltestosterone (an anabolic steroid, not testosterone replacement) may find it prudent to assess patients for vitamin A status and recommend concomitant supplementation with vitamin A and/or beta-carotene as indicated.

Mineral Oil

Agoral, Kondremul Plain, Liquid Parafin, Milkinol, Neo-Cultol, Petrogalar Plain.

	Potential or Theoretical Adverse Interaction of Uncertain Severity
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Mineral oil, as a lipid solvent, may absorb many substances and interfere with normal absorption of retinol, beta-carotene, and other nutrients.

Research

Some disagreement exists, but most research has found that mineral oil can interfere with the absorption of, and thus contribute to a depletion of, many nutrients, including beta-carotene, calcium, phosphorus, potassium, and vitamins A, D, K, and E. One study involving 25 children with chronic constipation found that a short course of mineral oil can reduce serum levels of beta-carotene while elevating serum retinol levels modestly. ⁷⁰

Nutritional Therapeutics, Clinical Concerns, and Adaptations

As a preventive and protective measure, health care professionals are advised to recommend regular use of a multivitamin supplement to patients using mineral oil for any extended period. Malabsorption of fat-soluble vitamins caused by ingestion of mineral oil can be minimized by administering mineral oil on an empty stomach or taking vitamin or mineral supplements at least 2 hours before or after the mineral oil. In general, internal use of mineral oil should be limited to less than 1 week.

Neomycin

Neomycin (Mycifradin, Myciguent, Neo-Fradin, NeoTab, Nivemycin); combination drugs: Adcortyl with Graneodin, Betnovate-N, Dermovate-NN, Gregoderm, Synalar N, Tri-Adcortyl, Trimovate.

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Probability: 2. Probable
Evidence Base:

AMPERSANDthinsp;

Consensus or

Preliminary

Effect and Mechanism of Action

Oral neomycin impairs absorption of vitamin A, especially in large doses. ^48,56

Research

In a rat model, Favaro et al. ⁷¹ observed that neomycin reduced the bioavailability of vitamin A by approximately 13% in both vitamin A–deficient and normal animals. In a double-blind trial involving five healthy male subjects, Jacobson et al. ⁷² observed a significantly reduced increase in plasma vitamin A levels in all study subjects subsequent to consuming a standard meal containing vitamin A (300,000 IU) when followed by neomycin sulfate (2 g) versus placebo.

The significance of this interaction on daily supplementation of vitamin A has not undergone further research and remains unknown. Nevertheless, this interaction hypothesis has largely settled into the status of consensus, even though evidence from clinical trials is minimal.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing neomycin internally for more than 2 to 3 days can advise patients of the probable benefit of supplementing with vitamin A (25,000 IU or 7.5 mg daily) or beta-carotene (25,000 IU or 15 mg daily). Individuals using neomycin topically will not experience problems related to malabsorption; likewise, adverse effects are unlikely to result from a single dose of oral neomycin as part of surgery preparation.

Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)

Ethinyl estradiol and desogestrel (Desogen, Ortho-TriCyclen). Ethinyl estradiol and ethynodiol (Demulen 1/35, Demulen 1/50, Nelulen 1/25, Nelulen 1/50, Zovia). Ethinyl estradiol and levonorgestrel (Alesse, Levlen, Levlite, Levora 0.15/30, Nordette, Tri-Levlen, Triphasil, Trivora). Ethinyl estradiol and norethindrone/norethisterone (Brevicon, Estrostep, Genora 1/35, GenCept 1/35, Jenest-28, Loestrin 1.5/30, Loestrin1/20, Modicon, Necon 1/25, Necon 10/11, Necon 0.5/30, Necon 1/50, Nelova 1/35, Nelova 10/11, Norinyl 1/35, Norlestin 1/50, Ortho Novum 1/35, Ortho Novum 10/11, Ortho Novum 7/7/7, Ovcon-35, Ovcon-50, Tri-Norinyl, Trinovum). Ethinyl estradiol and norgestrel (Lo/Ovral, Ovral). Mestranol and norethindrone (Genora 1/50, Nelova 1/50, Norethin 1/50, Ortho-Novum 1/50). Related, internal application: Etonogestrel/ethinyl estradiol vaginal ring (Nuvaring). See also Medroxyprogesterone earlier.

	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Potential or Theoretical Beneficial or Supportive Interaction, with Professional Management
	Potential or Theoretical Adverse Interaction of Uncertain Severity

Probability: 3. Possible or 2. Probable
Evidence Base:

AMPERSANDthinsp;

Emerging

Effect and Mechanism of Action

Oral contraceptive use has been associated with increased blood levels of vitamin A (and copper). ^73-75 Exogenous estrogen and progestin increase hepatic synthesis of retinol-binding protein (RBP), thus increasing the export of RBP-retinol complex in the blood.

Research

Several studies have reported an association between the use of OCs and increased serum levels of vitamin A. ^73,76,77 Horwitt et al. ⁷⁸ found that women using OCs had the lowest average levels of carotenoids corresponding to the highest average levels of vitamin A in the serum, and that estrogens seemed to increase the rate of conversion of carotene to vitamin A. The clinical implications of this potential interaction are uncertain at this time.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing exogenous estrogen and progestins for contraception may consider monitoring blood levels of vitamin A in patients, particularly in individuals with compromised liver function. Vitamin A supplementation may need to be avoided in some women; in others it might be indicated, depending on patient characteristics and response to the medication. Enhanced carotenoid intake (diet, supplementation) may be beneficial. Dietary intake of preformed vitamin A and provitamin A carotenoids, nutritional status, age and menstrual status, dose, form, and therapeutic intent all affect the degree to which OC administration alters vitamin A levels and function and whether this is beneficial, adverse, or insignificant.

Orlistat (Xenical)

Orlistat (alli, Xenical)

Drug-Induced Nutrient Depletion, Supplementation Therapeutic, Not Requiring Professional Management

Probability: 3. Possible (short term) or 4. Plausible (long term)
Evidence Base:

AMPERSANDthinsp;

Emerging

Effect and Mechanism of Action

As a gastrointestinal (GI) lipase inhibitor that reduces dietary fat absorption, orlistat can reduce the absorption of vitamin A and other fat-soluble nutrients.

Research

Melia et al. ⁷⁹ reported that orlistat had no significant short-term effect on blood levels of vitamin A in a small, open-label, placebo-controlled, randomized, two-way crossover study involving 12 healthy volunteers. Each participant received a single oral dose of 25,000 IU vitamin A, followed 24 hours later by a single oral dose of 400 IU vitamin E, on two separate occasions during oral administration of 120 mg orlistat or placebo three times daily for 9 days. A washout period of at least 2 weeks separated the two treatments. Based on subsequent analysis of serum concentrations of retinol, no significant effect was found on absorption of vitamin A during oral administration of 120 mg orlistat or placebo, although absorption of vitamin E was reduced significantly (by ∼43% on C ^max and ∼60% on AUC). In a multicenter, randomized, double-blind, parallel-group clinical trial involving 676 obese male and female subjects, Van Gaal et al. ^79a examined dose parameters, tolerability, and effects of orlistat over 6 months. Mean levels of vitamins A, D, and E and beta-carotene remained within the clinical reference ranges in all treatment groups and rarely required supplementation.

In a year-long multicenter study assessing the efficacy and tolerability of orlistat (120 mg three times daily) on weight loss in 228 obese adult patients Finer et al. ⁸⁰ coadministered vitamins A, D, and E to a small proportion of subjects “to maintain normal plasma levels of fat-soluble vitamins” and concluded that “fat-soluble vitamin supplements may be required during chronic therapy.” In a clinical trial involving seventeen obese African-American and Caucasian adolescents receiving orlistat, 120 mg three times daily, McDuffie et al. ⁸¹ observed several significant nutrient depletion patterns despite coadministration of a daily multivitamin supplement containing vitamin A (5000 IU), vitamin D (400 IU), vitamin E (300 IU), and vitamin K (25 µg). However, during 3 to 6 months of orlistat treatment, acute absorption of retinol was not significantly altered, and serum levels of vitamin A did not change significantly. In contrast, mean vitamin D levels were significantly reduced compared with baseline after 1 month of orlistat, despite multivitamin supplementation, and alpha-tocopherol absorption was significantly reduced, although serum levels were not significantly altered.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Although alpha-tocopherol, vitamin D, and beta-carotene status may be adversely affected by orlistat, the emerging evidence indicates it does not impact absorption enough to deplete serum retinol levels to a clinically significant degree, at least not in most patients over periods up to 12 months. The average hepatic storage of vitamin A can prevent deficiency for 2 years with no vitamin A intake and may significantly confound attempts to assess such interactions. Nevertheless, physicians prescribing orlistat may find it prudent to monitor relevant nutrient status, as well as suggest regular use of a multivitamin containing low to moderate dosages levels of vitamin A and other fat-soluble nutrients, when treating patients likely deficient in such nutrients and for whom extended use (>1 year) increases the risk of cumulative adverse effects.

Retinoids

Acitretin (Soriatane), bexarotene (Targretin); etretinate (Tegison), isotretinoin (13- cisretinoic acid; Accutane), tretinoin (all- transretinoic acid, ATRA; Atragen, Avita, Renova, Retin-A, Vesanoid, Vitinoin).

Potentially Harmful or Serious Adverse Interaction—Avoid

Probability: 2. Probable or 1. Certain
Evidence Base:

AMPERSANDthinsp;

Consensus (extrapolated);

Inadequate (direct)

Effect and Mechanism of Action

Tretinoin and other pharmaceutical retinoids are modified versions of the vitamin A molecule. For example, isotretinoin is an isomer of all- transretinoic acid (ATRA), a metabolite of retinol. A high dose intake of any retinoid (e.g., >50,000 IU daily) can result in accumulation and toxicity. An additive effect is predicted from concurrent intake of pharmaceutical retinoids and vitamin A supplements, based on structural similarities and known toxicities.

Research

Clinical research into interactions between and combined toxicity of retinol and retinoids has generally been avoided, regarded as unethical because of the apparently self-evident risk of clinically significant adverse effects. However, clinical trials do provide evidence of the impact of exogenous retinol sources on internal levels.

Rollman and Vahlquist ⁸² administered oral isotretinoin (0.5 mg/kg/day) for 3 months to 17 patients with severe acne vulgaris, then continued isotretinoin at a higher dose (0.75 mg/kg/day) to a subset of eight patients for an additional 3 months. After 3 months of therapy, epidermal retinol content increased by 53%, whereas dehydroretinol decreased by 79%. The researchers concluded that isotretinoin therapy interferes with the endogenous vitamin A metabolism in the skin. In a subsequent trial by this team involving 22 subjects with severe acne, administration of isotretinoin (1 mg/kg/day) for 4 months produced a marked increase in retinol and a decrease in dehydroretinol content in the skin. ⁸³

Clinical Implications and Adaptations

Even though no studies have confirmed adverse interactions, the structural similarities between and significant toxicities of both pharmaceutical retinoids and naturally occurring forms of vitamin A warrant caution. Consequently, supplementation of vitamin A by anyone using Accutane or related substances should be undertaken only under the supervision of an appropriately trained health care professional. These concerns are amplified for women of childbearing age because the risk of birth defects inherent to either substance is increased by their simultaneous use.

Physicians prescribing retinoids are advised to ask patients about use of vitamin supplements. Conservative practice suggests avoidance of supplemental vitamin A (particularly >10,000 IU/day) while taking Accutane or other retinoids. Most multivitamin formulations will be within the range generally considered as safe. Nevertheless, patients should watch for signs of toxicity. Headache is a common adverse effect associated with vitamin A toxicity; bone pain, dry scaly skin, and hair loss are other potential symptoms.

Some retinol is metabolized into retinoic acid, but in the absence of retinol deficiency, minimal beta-carotene (or alpha-carotene) is metabolized into retinol. Thus, current knowledge indicates that beta-carotene supplementation introduces no known risk of contributing to cumulative retinol toxicity through an additive interaction.

Tetracycline Antibiotics

Evidence: Minocycline (Dynacin, Minocin, Vectrin). Extrapolated: Demeclocycline (Declomycin), doxycycline (Atridox, Doryx, Doxy, Monodox, Periostat, Vibramycin, Vibra-Tabs), oxytetracycline (Terramycin), tetracycline (Achromycin, Actisite, Apo-Tetra, Economycin, Novo-Tetra, Nu-Tetra, Sumycin, Tetrachel, Tetracyn); combination drugs: chlortetracycline, demeclocycline, and tetracycline (Deteclo); bismuth, metronidazole, and tetracycline (Helidac).

	Minimal to Mild Adverse Interaction—Vigilance Necessary
	Potentially Harmful or Serious Adverse Interaction—Avoid

Probability: 2. Probable or 1. Certain
Evidence Base:

AMPERSANDthinsp;

Consensus (extrapolated);

Preliminary (direct)

Effect and Mechanism of Action

Benign intracranial hypertension and pseudotumor cerebri (PTC) have been associated with both hypervitaminosis A and tetracycline use independently. Vitamin A may potentiate the development of intracranial hypertension when taken in combination with tetracycline antibiotics. The development of severe headaches and PTC (or benign intracranial hypertension) have been associated with such concurrent use. ^84,85

Reports

Use of retinoids, particularly Accutane, has been associated with a number of cases of pseudotumor cerebri, some of which involved concomitant use of tetracyclines. First described by Gerber et al. ⁸⁶ in 1954, PTC or benign intracranial hypertension has long been associated with vitamin A administration. ^87,88 PTC occurs in 30% to 50% of patients with hypervitaminosis A and has been associated with isotretinoin therapy and etretinate in particular. ^85,89-91 Combination therapy with tetracyclines may increase the risk of occurrence. Typical symptoms include papilledema, vision problems, nausea, and severe headaches. However, three specific criteria constitute its clinical characterization: (1) neurological and ocular symptoms and signs of increased intracranial pressure, which may include headache, nausea, transient visual obscurations, sixth-nerve palsies, and papilledema; (2) radiologically demonstrable normal or small cerebral ventricles; and (3) elevated cerebrospinal fluid (CSF) pressure. ^92,93

Moskowitz et al. ⁹⁴ published a case report describing a 16-year-old girl who developed headaches and double vision after starting treatment for acne with vitamin A and minocycline; these adverse effects resolved once the compounds were discontinued. Further research is warranted to determine whether the symptoms could have been caused by an interaction between vitamin A and the drug.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Despite minimal direct evidence, conservative practice warrants avoidance of concomitant treatment with tetracycline antibiotics and vitamin A, based on functional equivalence of vitamin A and pharmaceutical retinoids and standard contraindications against coadministration of tetracyclines and such agents. Physicians prescribing antibiotics, particularly tetracyclines, need to ask patients about supplement use, particularly self-administration of vitamin A; tetracycline antibiotics and vitamin A are both used for acne vulgaris. Patients should be advised to limit supplemental retinol to 10,000 IU or less and to watch for signs of toxicity. Headache is a common adverse effect associated with vitamin A toxicity, as are bone pain, dry scaly skin, and hair loss.

Erythromycin can serve as an effective alternative to the tetracycline family and is less likely to produce serious adverse interactions, when antibiotic therapy is considered imperative.

Current knowledge indicates that in the absence of retinol deficiency, minimal beta-carotene (or alpha-carotene) is metabolized into retinol. Thus, beta-carotene supplementation does not contribute to cumulative retinol toxicity, although evidence of its efficacy in treating acne vulgaris is relatively weak compared with that supporting the use of retinol and related substances.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Antibiotics

Concomitant use of vitamin A with antibiotics has been proposed as efficacious in the treatment of shigellosis. Compromised nutritional status can play a significant role in susceptibility to many infections, and vitamin A is well known for its ability to reduce risk and assist treatment of many viral and bacterial infections. The use of vitamin A with antibiotic therapy represents an area of potential synergy in integrative therapeutics. However, systematic research is only beginning, and a wide range of clinical trials will be necessary before substantive conclusions can be made on nutritional synergies in antibiotic-treated bacterial infections.

In a randomized, double-blind, controlled clinical trial involving 83 children in Bangladesh, age 1 to 7 years, with acute shigellosis but no clinical signs of vitamin A deficiency, Hossain et al. ⁹⁵ investigated the efficacy of a single, large oral dose of vitamin A. Nalidixic acid (55 mg/kg/day, every 6 hours), or an alternative determined by sensitivity test, was administered to all subjects. Of these, 42 received a single oral dose of 200,000 IU of water-miscible vitamin A as retinyl palmitate plus 25 IU of vitamin E; the 41 subjects in the control group received 25 IU of vitamin E. Subjects were evaluated after 5 days for evidence of “bacteriological cure.” The researchers concluded that a single oral dose of 200,000 IU vitamin A can hasten clinical cure in acute shigellosis, can reduce its severity by promoting repair of the colonic mucosa and stimulating the immune system, and was especially relevant for children in areas with widespread vitamin A deficiency.

Salam et al. ⁹⁶ criticized the previous study's design and the interpretation of the findings, emphasizing that the antibiotic used did not provide adequate antimicrobial treatment for most of the patients. They stated that the original authors’ conclusions were not supported by the data, and that the potential clinical benefit of adjuvant vitamin A administration could not be proved without significant changes in study design and further research.

See also Tetracycline Antibiotics and Neomycin sections.

Anticonvulsant Medications, Including Phenobarbital, Phenytoin, and Valproic Acid

Evidence: Carbamazepine (Carbatrol, Tegretol), divalproex semisodium, divalproex sodium (Depakote), ethosuximide (Zarontin), phenobarbital (phenobarbitone; Luminal, Solfoton), phenytoin (diphenylhydantoin; Dilantin, Phenytek), sodium valproate (Depacon), valproic acid (Depakene, Depakene Syrup), valproate semisodium.

Extrapolated, based on similar properties: Clonazepam (Klonopin), clorazepate (Tranxene), ethotoin (Peganone), felbamate (Felbatol), fosphenytoin (Cerebyx, Mesantoin), gabapentin (Neurontin), lamotrigine (Lamictal), levetiracetam (Keppra), mephobarbital (Mebaral), methsuximide (Celontin), oxcarbazepine (Trileptal), pentobarbital (Nembutal), piracetam (Nootropyl), primidone (Mysoline), topiramate (Topamax), trimethadione (Tridione), vigabatrin (Sabril), zonisamide (Zonegran).

Conventional practice regards both vitamin A and anticonvulsant drugs as carrying significant risks of teratogenic adverse effects, especially when taken in high doses during pregnancy, although the mechanism involved has thus far eluded researchers. Preliminary evidence suggests that anticonvulsant medications can significantly alter endogenous retinoid metabolism in several ways. In particular, numerous studies have found that antiepileptic drugs (AEDs) alter endogenous retinoid concentrations, and that this effect could provide a possible mechanism for the pattern of teratogenesis observed with anticonvulsant therapy.

Although birth defects have been presented as a significant risk of high levels of vitamin A intake, other research indicates that supplemental vitamin A might prevent birth defects in children born to women receiving multiple-anticonvulsant therapy. All- transretinoic acid (ATRA) and other vitamin A metabolites significantly influence embryonic development (e.g., growth, differentiation, morphogenesis), and imbalances in vitamin A status, both excess and deficiency, have been associated with teratogenic effects. Thus, medications such as AEDs that disrupt healthy levels of plasma retinoids could result in adverse effects, which could vary depending on the pathophysiology of the patient's underlying disorder(s), the medications and dosage levels being used, as well as the clinical response, nutritional status, general state of health, and other characteristics of the mother.

Evidence indicates that the toxicity of anticonvulsant drugs, and most likely some of their teratogenic effect, may be related to low blood levels of vitamin A. Nau et al. ⁹⁷ measured plasma levels of retinol and its oxidative metabolites all- trans, 13- cis, and 13- cis-4-oxo retinoic acid in 75 infants and children treated with various AEDs for seizures and in 29 untreated controls of comparable age. Retinol levels increased with age, whereas the concentrations of retinoic acid compounds did not exhibit age dependency. Valproic acid monotherapy increased retinol levels in the young age group, and a trend toward increased retinol concentrations was seen in all other patient groups. The authors also noted significant declines in plasma levels of 13- cisand 13- cis-4-oxo retinoic acid in all patient groups treated with phenytoin, phenobarbital, carbamazepine, and ethosuximide, in combination with valproic acid, to levels below one third and one tenth of corresponding control values, respectively. Only minor changes were observed with ATRA, except in one patient group treated with valproic acid plus ethosuximide who demonstrated increased levels of this retinoid.

The available research does not conclusively answer whether coadministration of anticonvulsants and vitamin A inherently results in adverse effects or increases the risk of birth defects when taken during pregnancy. Because both retinoids and AEDs are highly associated with teratogenicity, clinical trials adding retinoid to AEDs in pregnant epileptic women are unlikely and inadvisable. Ultimately, characterization of these interactions remains important for understanding pharmacology and physiology, but it does little to change the recommendations of clinicians for their female patients of childbearing age; that is, neither anticonvulsants nor moderate to high doses of vitamin A should be considered as safe during pregnancy; and alternative therapeutic strategies of lesser toxicity are required.

Furthermore, these cautions need to be extended because of “off-label” prescribing of medications broadly classified as “anticonvulsants.” These medications may be more often prescribed for pain, insomnia, anxiety, migraines, postherpetic neuralgia, and conditions other than seizure disorders. For example, up to 90% of gabapentin (Neurontin) is prescribed for off-label purposes, which are aggressively promoted by drug manufacturers and marketers. Such off-label use, however, is generally for conditions with less serious consequences than uncontrolled seizure disorders, and thus continued medication use during pregnancy is less likely to occur for such conditions.

Arachidonic Acid Cascade Inhibitors

5,8,11,14-Eicosatetraenoic acid, curcumin, indomethacin, l-phenyl-3-pyrazolidone (phenidone), nordihydroguaiaretic acid (NDGA).

Based on the findings of previous in vivo research Spingarn et al. ⁹⁸ conducted in vitro studies on the potential synergistic effects of combining 13- cisretinoic acid (a retinoid, Accutane) and arachidonic acid cascade inhibitors (AACIs) on growth of head and neck squamous cell carcinoma (HNSCC). First, they investigated the effects of several AACIs (indomethacin, curcumin, phenidone, nordihydroguaiaretic acid, and 5,8,11,14-eicosatetraenoic acid) and 13- cisretinoic acid on the growth of two HNSCC cell lines and found that AACIs caused dose-dependent growth inhibition of both cell lines. When they combined these substances with 13- cisretinoic acid, they found that, except for indomethacin, they were able to inhibit HNSCC cell growth at lower concentrations of these drugs.

Although provocative and encouraging, this initial research has not yet matured to the level necessary for practical implementation in a clinical setting. Furthermore, because this research involved 13- cisretinoic acid, rather than a standard supplemental form of vitamin A, any extrapolation to such forms of vitamin A are not directly supported by the available evidence. Oncologists might consider discussing the potential benefit of such experimental adjunctive treatment options with patients. Such coadministration would necessitate close monitoring in conjunction with health care professionals trained and experienced in nutritional therapeutics, preferably within the context of a coordinated integrative care facility. Further research is warranted.

Methotrexate

Methotrexate (Folex, Maxtrex, Rheumatrex).

Vitamin A plays an important role in the function of healthy skin and proper function of the immune system. Both vitamin A and methotrexate are used in the treatment of psoriasis; methotrexate is also used against many other conditions, including malignant tumors. Nakagawa et al. ²⁵ found that coadministration of methotrexate and retinyl palmitate enhanced antitumor activity in mice bearing ascites sarcoma 180 or P388 leukemia.

These preliminary findings suggest potential value in further study using well-designed research. Physicians prescribing methotrexate might consider coadministration of vitamin A within the context of close supervision and regular monitoring by health care professionals experienced in both conventional pharmacology and nutritional therapeutics.

Tamoxifen

Tamoxifen (Nolvadex).

Tamoxifen is an estrogen antagonist, specific for estrogen-driven cancers, and not a form of cytotoxic chemotherapy per se. Thus it needs to be treated separately from the agents discussed earlier under chemotherapy.

Some clinical oncologists experienced in the treatment of breast cancer patients with integrative therapeutics have used high-dose emulsified vitamin A in conjunction with tamoxifen. This form of vitamin A is significantly less likely to produce as much hepatic retinyl ester accumulation, with dosage levels as high as 1 million U/day administered until significant cheilosis developed, then cut to 100,000 IU/day and gradually increased again. Close monitoring of the blood retinol level is essential, especially since it is typically pushed to or slightly beyond the upper limit of normal. Likewise, it is necessary to monitor skeletal metabolism and adjust vitamin A intake as needed to prevent bone loss. In an anecdotal report, one patient developed liver damage from long-term use of 25,000 IU nonemulsified vitamin A along with tamoxifen. ⁹⁹ Further research into efficacy, safety, and factors influencing individual appropriateness is warranted through well-designed clinical trials, preferably within the context of integrative oncology care involving health care professionals trained and experienced in conventional pharmacology and nutritional therapeutics.

Thioridazine

Thioridazine (Mellaril).

Curtis and Swicord ¹⁰⁰ stated that patients taking thioridazine exhibited elevated plasma vitamin A concentrations compared with individuals not using the medication. The clinical implications of this reported phenomenon, as well as its frequency and patterns of individual susceptibility, remain to be investigated. Well-designed clinical trials and thorough documentation of case reports are needed to determine whether this potential interaction might result in clinically significant effects. Pending such evidence, physicians prescribing thioridazine, and possibly other phenothiazines, are advised to ask patients about supplement intake, educate regarding signs and symptoms of vitamin A toxicity, and monitor those individuals for whom concurrent use appears appropriate but risky.

Anisindione (Miradon), dicumarol, ethyl biscoumacetate (Tromexan), nicoumalone (acenocoumarol; Acitrom, Sintrom), phenindione (Dindevan), phenprocoumon (Jarsin, Marcumar), warfarin (Coumadin, Marevan, Warfilone).

Vitamin A may increase the anticoagulant effects of warfarin or related anticoagulant medications. Physicians are advised to ask all patients about supplement intake, and vitamin A dosage should be noted. Despite minimal corroborating evidence, doses of vitamin A greater than 750 µg (2500 IU) have been reported to induce a hypoprothrombinemic response. ¹⁰¹ Long-term use of vitamin A or use of high doses may lead to an increased risk of bleeding for those taking anticoagulant medications, particularly warfarin.

The clinical significance and frequency of occurrence of this possible interaction are uncertain, even with several case reports. Physicians prescribing warfarin need to be aware of the risk of altered treatment effect when vitamin A is coadministered and closely monitor such patients for increased effects. International normalized ratio (INR) levels and prothrombin time (PT) need to be checked with greater frequency during the first 2 weeks after either starting or stopping vitamin A, particularly at high doses, to verify that the risk of bleeding or clotting (as reflected by the INR value) is not being affected by the nutrient. In general, it is important always to monitor PT twice weekly when medications, supplements, and diet are changed; this is the safest and most reliable method of compensating for unexpected or idiosyncratic interactions in patients undergoing treatment with coumarin derivatives.

nutrient-nutrient interactions

Calcium

Because growing evidence indicates that excessive vitamin A intake may promote bone loss, the concomitant increase of calcium intake in conjunction with vitamin D support (through diet, supplements, and sunlight, titrating to blood level of 25-hydroxyvitamin D) is to be encouraged with high-dose administration of retinoids more than briefly.

Iron

Vitamin A deficiency may exacerbate iron deficiency anemia. Research involving anemic children indicates that concomitant intake of iron and vitamin A supplements enhances treatment of iron deficiency more effectively than iron supplementation alone. ¹⁰² Suharno et al. ¹⁰³ reported similar findings in research involving treatment of pregnant women with “nutritional anemia” in West Java, Indonesia. Vitamin A supplementation can also improve iron status in populations, especially children, when poor nutritional status, including iron deficiency, is related to helminthiasis, as discussed earlier. ¹⁸ Conversely, Muñoz et al. ¹⁰⁴ found that supplementation with iron and zinc improved indicators of vitamin A status in Mexican preschoolers.

Vitamin D

Vitamin A may antagonize the action of vitamin D. ⁷

Vitamin E

Large doses of vitamin E can interfere with the absorption of vitamin A.

Zinc

Zinc deficiency appears to interfere with vitamin A metabolism through several mechanisms, including its absorption, transport, and utilization. Zinc binds with the transporter protein RBP, which is then able to transport vitamin A from liver stores to cells and tissues of numerous organs. Consequently, zinc deficiency results in decreased synthesis of RBP, thus affecting transport of retinol to target tissues. Zinc deficiency results in decreased activity of retinyl-palmitate esterase, the hepatic enzyme that releases retinol from retinyl palmitate, its storage form. Zinc is also required for retinol dehydrogenase, the enzyme involved in the oxidative conversion of retinol into retinal. ^1,105

As noted, Muñoz et al. ¹⁰⁴ found that administration of zinc and iron improved indicators of vitamin A status in Mexican preschoolers. However, most human studies have shown only a weak link between vitamin A and zinc status. Thus far, animal and human studies have not conclusively differentiated responses related to zinc deficiency from generalized protein-energy deficiency. In disease states in which liver function is severely compromised and both zinc and vitamin A metabolism and transport are impaired, serum zinc and vitamin A concentrations tend to be positively correlated. More research is warranted to understand further the apparent synergy between these two nutrients, its mechanisms, and contextual influences, particularly individual variations and coexisting, moderate to severe, zinc and vitamin A deficiencies.

Citations and Reference Literature

1.Russell RM. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr 2000;71:878-884.View Abstract
2.Melhus H, Michaelsson K, Kindmark A et al. Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med 1998;129:770-778.View Abstract
3.Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA 2002;287:47-54.
4.Binkley N, Krueger D. Hypervitaminosis A and bone. Nutr Rev 2000;58:138-144.View Abstract
5.Promislow JH, Goodman-Gruen D, Slymen DJ, Barrett-Connor E. Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. J Bone Miner Res 2002;17:1349-1358.View Abstract
6.Michaelsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of fracture. N Engl J Med 2003;348:287-294.View Abstract
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Vitamin A with Chemotherapy in Treatment of Late-Stage Breast Cancer

Antioxidants and Chemotherapy

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