Vitamin A Use Today and Its Potential Toxicities

Introduction

Deficiency of vitamin A is rare in the United States, yet many people take supplemental vitamins that contain vitamin A to prophylactically manage what potentially may ail them. Vitamin A has received much attention, both in the scientific and lay press, that is established in fact, assumption, misinformation, as well as hype. Recent findings on the nutritional and metabolic differences between young and old persons have raised the concern of vitamin A toxicity. Therefore, healthcare professionals should be cognizant of the physiology of retinol, and the benefits and risks of supplementation.

Vitamin A and its natural and synthetic analogs are referred to as retinoids. There are several forms of retinoids: retinal (aldehyde); retinoic acid, which is also known as tretinoin (acid); and retinol (alcohol). Vitamin A is acquired through the diet and is ingested through animal sources as retinyl esters and through plant sources as carotenoids, and converted to retinol (Figure).¹

Vitamin A is a group of compounds that plays an important role in vision, bone growth, reproduction, cell division, and cell differentiation. It helps regulate the immune system and may help lymphocytes. Vitamin A is found commonly in many animal and plant food sources and is a common component of fortified foods. In addition to foods, vitamin A is a common component of vitamin and mineral supplements.

Consumption of vitamin and mineral supplements is a common behavior in the United States, especially in older adults. Vitamin and mineral supplement use is the third largest over-the-counter drug category, with approximately $1.5 billion spent annually.² Reasons for taking these supplements include decreasing susceptibility to health problems such as stress, colds, heart attacks, and cancer, and increasing energy.

Vitamin A in Animal and Plant Food Sources

Vitamin A found in foods that come from animals is called preformed vitamin A (Table I).³ It is absorbed in the body in the form of retinol. Retinol, one of the most usable (active) forms and the most reduced form of the vitamin, satisfies requirements for all known functions of vitamin A. Sources include liver, whole milk, and some fortified food products. The body can convert retinol into the other active forms, retinal and retinoic acid.¹

Vitamin A that is found in colorful fruits and vegetables is called provitamin A carotenoid.³ Twenty-six percent of vitamin A consumed by men and 34% of vitamin A consumed by women is in the form of provitamin A carotenoids.³ Common provitamin A carotenoids found in foods that come from plants are beta-carotene, alpha-carotene, and beta-cryptoxanthin. Among these, beta-carotene is most efficiently made into retinol. Alpha-carotene and beta-cryptoxanthin are also converted to vitamin A, but only half as efficiently as beta-carotene.¹

Fewer than 10% of the 563 identified dietary carotenoids can be made into vitamin A in the body. However, these carotenoids are powerful antioxidants with greater protective effects against free radical damage than beta-carotene. Lycopene, lutein, and zeaxanthin are carotenoids that do not have vitamin A activity but have other health-promoting properties.

Measurements of Vitamin A Activity

Vitamin A activity is measured relative to retinol as retinol equivalents (RE). One RE is equal to 1 microgram (mcg) of retinol. International unit (IU) is a measurement of vitamin A commonly used for vitamin A supplement products. One RE of vitamin A (in mcg) equals:

• 6 IU from beta-carotene
• 10 IU from other carotenoid-rich plant foods
• 4.10 IU from milk and yogurt
• 3.33 IU from animal sources and fortified foods

Food Labeling of Vitamin A

In 2001, the Institute of Medicine (IOM) lowered the Recommended Dietary Allowance (RDA) for vitamin A to 900 mcg (3000 IU) for males and 700 mcg (2310 IU) for females.⁵ The Tolerable Upper Intake Level (UL), which sets the toxicity risk level for vitamin A, is set at 3000 mcg (10,000 IU) per day for both males and females (Table II).⁵ The RDA value used on food labels is the 1989 value of 1500 mcg (5000 IU), and toxicity is set at 4500-7500 mcg (15,000-25,000 IU). The RDA and the Daily Value (DV) shown on food labels actually conflicts with current recommendations. The consumer who measures his or her daily intake of vitamin A by the DV percentage appearing on food labels could easily consume more than the RDA, and possibly come close to the UL.⁶

The 1989 RDA value used on the food label for vitamin A is overly generous for older adults.⁷ The 1989 RDA Committee found insufficient data to create additional age categories for the age groups 51-70 years and 71 years or older. In the 1989 RDA tables, values for only a few nutrients differed between persons age 23-50 years and those age 51 years or older. The data examined by the 1989 RDA Committee for the most part were not derived from studies on older adults but were data extrapolated from younger adult values. The RDA values established for the 2001 Dietary Reference Intakes considered data from studies in older adults.⁸

Food Fortification

Some foods have long been vitamin A–fortified, including milk, some margarine, instant oats, and ready-to-consume breakfast cereals. Recently, however, other foods have been fortified with relatively high amounts of vitamin A, as well as with other vitamins. These include cereal bars, energy bars, and candy. The decision regarding which foods are fortified, the amount of fortification, and the form of vitamin A that is used is not regulated; rather, individual manufacturers are free to make these decisions.⁶

Supplements

Some vitamin D supplements include preformed vitamin A. Consumers seeking a vitamin D supplement might not examine the labels of these supplements closely and could unwittingly choose one that also contains vitamin A. Fish liver oil and fish liver oil capsules, such as those from cod or halibut liver, also contain appreciable amounts of preformed vitamin A. With recent attention to the benefits of omega-3 fatty acids such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from fish oils, consumers intending to purchase DHA and/or EPA supplements, which do not contain vitamin A, in an effort to increase their dietary intakes of these fatty acids may choose fish liver oil supplements containing vitamin A instead.⁶

The IOM encourages consumption of all carotenoid-rich fruits and vegetables for health-promoting benefits. Recent research indicates that supplements in the form of whole food extracts rich in antioxidants may possibly have benefit in humans.⁹ This research, however, is based on animal studies, and until there is strong evidence in humans, these findings should not be taken as an endorsement of supplements.

Clinical Application

Clinical application of oral retinoids include the use of megadose vitamin A for the treatment of age-related macular degeneration (ARMD). The Age-Related Eye Disease Study (AREDS),¹⁰ a clinical trial that was sponsored by the National Eye Institute, revealed that taking high levels of antioxidants and zinc can reduce the risk of developing advanced ARMD and its associated vision loss. The AREDS formulation used in the study included 15 mg of beta-carotene, which is equivalent to 25,000 IU of vitamin A.

Isotretinoin is a retinoid that is Food and Drug Administration (FDA)–approved to be given orally for recalcitrant severe nodular acne. Incidentally, it is prescribed more and more frequently for less severe acne. In addition, although there have not been significant numbers of older adults in clinical trials evaluating the use of isotretinoin, it has been used in this age range.

There are several topical retinoids available. Topical retinoids are prescribed widely both for diseases that have been FDA–approved, as well as for evidence-based off-label uses. A popular prescription is tretinoin, which is commonly used for the treatment of acne. All-trans retinol is a parent form of vitamin A, which is a weaker form of the prescription tretinoin and is added to many over-the-counter topical beauty products.¹¹ When it is applied topically to the skin, it diffuses as a fat-soluble drug and is oxidized to form all-trans retinoic acid.¹² Vitamin A compounds are also used to treat several types of malignancies.

Precautions in Prescribing Vitamin A

The therapeutic window for medicinal benefit is narrow, particularly when addressing the comorbidities of many older adults and the combined effect of all medications, both prescribed and over-the-counter, as well as dietary intake. There is a tendency in the older population for overuse of supplements. Supplement use in general is associated with high intakes of vitamin A. Most multivitamins specify the type and amount of vitamin A contained in the product. Although some major vitamin manufacturers now provide 20-25% of the vitamin A as beta-carotene as part of the source, preformed vitamin A (usually as retinyl acetate or palmitate) tends to predominate.

A widely referenced article published in the Journal of the American Medical Association advocated that all adults take a multivitamin daily and suggested a daily dose of two multivitamins for older adults.¹³ The recommendation for those of advancing age was based on the high prevalence of low vitamin B₁₂ and vitamin D intakes in this age group. This practice places the older adult at even greater risk of hypervitaminosis A, given that the DV on supplements is based on an RDA, which is higher than current recommendations; hence, this approach should be discontinued.^6,14

Furthermore, chronic renal disease may also result in significantly elevated serum retinol levels and should be taken into consideration.¹⁵ Smokers should be advised to take formulations without beta-carotene, as the incidence of lung cancer appears to be greater in smokers who take a daily supplement of beta-carotene.^4,16 There is at least one study that revealed a potential interaction of ethanol with beta-carotene that delayed blood clearance and enhanced hepatotoxicity; therefore, those who consume alcohol should also be cautioned.¹⁷

Synthetic retinoids, derivatives of vitamin A, are manufactured into a cream or gel such as isotretinoin and tretinoin. Any additional intake of vitamin A (retinol) should be avoided when using these products due to some systemic absorption. It is known that serum levels are minimally affected by topical application of tretinoin, and case reports do exist describing topical tretinoin-induced teratogenesis.¹⁸

Susceptibility of Older Adults to Vitamin A Toxicity

Research suggests that those of advancing age may require less vitamin A than younger adults because of higher circulating levels.¹⁹ Body retention of vitamin A is likely enhanced with aging. The liver is the primary storage organ for vitamin A, containing approximately 80% of total body reserves. With advancing age, both mean and median liver values for vitamin A do not decrease despite indication that dietary intake of vitamin A decreases. The National Health and Nutrition Examination Survey (NHANES) indicates that 42-65% of older Americans eat less than two-thirds of the current RDA for this vitamin.² It is suspected that reasons for well-maintained body stores (despite diminished dietary intake) might be that vitamin A intestinal absorption may increase with age or that reduced chylomicron clearance of vitamin A may exist.⁸

Animal studies indicate that uptake and absorption of vitamin A by the intestine increase with age. Russell⁸ compared blood response curves after feeding physiologic doses of vitamin A to young and older adults, and found that the latter had significantly higher blood responses than did the former. This could be due to either increased absorption or decreased clearance by peripheral tissue. Additional studies indicated that young adults were able to clear reinfused vitamin A twice as quickly as the older adults.^19,20

The significance of the decreased clearance is that when retinyl esters remain in serum associated with chylomicron remnants for any length of time, they begin to transfer to low-density lipoproteins and gradually become transformed to retinol, a nonspecific delivery system for vitamin A that is toxic to cell membranes.^8,20,21

Clinical Manifestations of Vitamin A Toxicity

Patients with vitamin A toxicity can present with variable signs and symptoms, and the manifestation of acute and chronic toxicities may overlap.²² The diagnosis of hypervitaminosis A can be missed in the older adult because signs and symptoms of its diffuse organ system involvement are otherwise often encountered in this population. Musculoskeletal and generalized complaints such as weakness, malaise, weight loss, myalgia, arthralgia, and bone pain may be present. Neurologic symptoms such as headache, drowsiness, blurred vision, and signs of increased intracranial pressure may occur. Skin manifestations are numerous and can include desquamation, pruritis, alopecia, and brittle nails. Gastrointestinal findings could encompass anorexia, abdominal pain, diarrhea, and hepatotoxicity, which can lead to cirrhosis if vitamin A toxicity is prolonged.^22,23 Vitamin A also stimulates osteoclast formation and can predispose older adults to fragility fractures.²⁴ Isotretinoin has been noted to cause marked elevations in triglyceride and cholesterol levels, but this may be transient.²⁵

Acute toxic events may occur with ingestion of more than 100 times the RDA over a period of hours or a few days.²⁶ Chronic toxicity can result after prolonged ingestion of 25,000 IU per day or as low as 5000 IU per day if factors that augment the toxic effects of vitamin A are present, including comorbid liver or renal disease, alcoholism, protein malnutrition, and vitamin D supplementation.²⁷ Management of vitamin A toxicity includes ensuring that all vitamin A products are discontinued, including multivitamins and topical creams; otherwise, there is no specific intervention to remove vitamin A from the body. Resuscitative and supportive care as needed should be provided for any sequalae such as dehydration, altered mental status, hypercalcemia, and hepatotoxicity. In general, it appears that monitoring serum vitamin A (retinol) level has little predictive value of toxicity, and one may need to rely on clinical suspicion, especially when following patients at risk.²⁷ However, even if low or normal values may not be very sensitive, sound judgment suggests that high levels would be supportive of the diagnosis of hypervitaminosis A, and intervention needs to be pursued. This ideology would be analogous to that of working up a disorder and finding a normal erythrocyte sedimentation rate, which may not be helpful in confirming a diagnosis, but yet an extremely high value would certainly prompt further evaluation.

Consumption of large amounts of dietary carotenoids will not contribute to vitamin A toxicity since efficiency of absorption decreases with dosage, and conversion to the vitamin is not rapid enough to contribute to toxic levels; however, beta-carotene supplements are not without concern.⁴ Excessive ingestion of vegetables and fruits that contain carotene can result in elevated levels of carotene. Although considered benign, carotenemia is manifested as a yellow-orange coloration of the skin, and in dark-complexion individuals this is particularly noticeable on the palms and soles. This is not to be confused with jaundice and can be easily differentiated by physical examination of the sclera. The sclera tissue is rich in elastin, which has a high affinity to bilirubin; hence, the sclera will be icteric in those with jaundice and spared in carotenemia. Management of carotenemia involves reducing or eliminating carotene from the diet. Disappearance of the discoloration may take a few months due to its accumulation in fat tissue. Monitoring vitamin A or carotene levels is not helpful. Adverse effects and toxicity of megadoses of beta-carotene for protracted periods of time (ie, beyond a decade) have not been fully determined.

Summary

Vitamin A has several medicinal uses; however, many older adults also use vitamin A prophylactically. This article should not be taken as an endorsement of supplements. It is most appropriate that healthcare providers have a full awareness of what is available and be cognizant of their patients’ personal usage. Healthcare professionals should include questions about the use of dietary supplements as well as topical preparations when obtaining a medical history from their older adult patients. All dietary supplements should clearly list ingredients and known contraindications. Patients planning to use supplements and other preparations should first have their dietary practices and lifestyles evaluated by a healthcare professional.² In addition, patients should be counseled regarding symptoms of toxicity and to avoid concomitant use of other vitamin A–containing products when prescribed megadose retinoids for medicinal use.

The authors report no relevant financial relationships.

Dr. McClure is Mirick-Myers Endowed Chair for Geriatric Medicine, Division Chief, Geriatrics, and Professor of Medicine, Texas Tech University Health Sciences Center School of Medicine, Amarillo; Dr. Chauncey is Professor of Clinical Family Medicine, Texas Tech University Health Sciences Center School of Medicine, Department of Family and Community Medicine, Lubbock; and Mr. Nipp is a medical student, Texas Tech University Health Sciences Center School of Medicine, Amarillo.