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.

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.

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

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.

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