Sources and Physiologic Functions:
Sources: Foods that are rich in vitamin A are milk, cheese, butter, eggs, liver, and such fish as herring, sardines, and tuna. The richest sources of vitamin A are the liver oils of shark, halibut, and polar bear. Rich sources of pre-vitamin A are spinach, carrots, papaya, oranges, sweet potatoes, and cantaloupes. Poor sources of vitamin A and pre-vitamin A are vegetable oils, white lard, white corn, cereals, beef, and legumes.
International Units (IU)
Milk 2% 8 fl oz – 500IU; Cream Cheese 1oz 405IU; Cheddar Cheese 3.5 oz 1059IU; Egg (boiled) 1 medium 280IU; Egg (scrambled) 1 medium 416IU; Liver (beef braised) 3.5 oz 35679IU; Liver (veal braised) 3.5 oz 26883IU; Herring (raw) 3.o oz 80IU; Herring (kippered) 1 piece 51IU; Sardines (canned/oil) 2 pieces 54IU; Tuna (raw) 3.0 oz 50IU; Tuna (canned) 3.0 oz 16IU; Pre-Vitamin A (b-carotene) Spinach (boiled) ½ cup 7371IU; Spinach (raw) ½ cup 1880IU; Carrots (raw) 1 medium 2025IU; Carrots (boiled) ½ cup 19152IU; Papaya (raw) 1 medium 863IU; Oranges 1 fruit 240IU; Sweet potatoes (baked w/skin) 1 medium 24877IU; Sweet potatoes (boiled w/o skin) 1 medium 27969IU; Cantaloupes 1 cup 5158IU; Parsley ½ cup freeze dried 885IU
Biochemistry: Vitamin A is a fat-soluble vitamin. Vitamin A is a collective term for retinal, retinol, retinoic acid, and b-carotene. The vitamin A in foods of animal origin, such as eggs, milk, butter, and liver, occurs largely in the form of retinyl esters. A retinyl ester is a molecule of retinol esterified with a molecule of a fatty acid, such as palmitic acid. The fatty acid is bound to the hydroxyl group of retinol. Plants do not contain vitamin A; however, some plants are rich sources of pre-vitamin A. Pre-vitamin A takes the form of a family of compounds called the carotenoids. More than 500 carotenoids occur in nature, though only about 50 of them can be used as precursors of vitamin A. The most important of these is all-trans-b-carotene. The prefix all-trans indicates that all of the double bonds are in the trans conformation rather than the cis conformation. Vegetables that are dark green, orange, and yellow are rich sources of the carotenoids. Other forms of pre-vitamin A are cryptoxanthine and a-carotene. Some carotenoids cannot be converted to vitamin A by mammals. These include lutein, lycopene, and canthaxanthine.
Vitamin A serves three classes of functions: support of epithelial cells (lungs and tracheal integrity), fetal growth and vitality of the testes, and utilization in the visual cycle. Dietary retinoic acid can support only the first function. Retinoic acid cannot be stored in the liver. Retinyl esters, retinol, and retinal are interconvertible. Retinal can be oxidized to form retinoic acid. All three functions of vitamin A can be supported by dietary retinyl esters, retinol, or retinal. Although these forms can be converted to retinoic acid, retinoic acid apparently cannot be reduced to form retinal. Dermatological problems like acne, psoriasis, Darier’s disease, and skin aging are effectively treated with retinoic acid and topical tretinoin.
Populations at risk: In the United States, patients suffering from chronic intestinal disease, malignancy, malaria, pneumonia, and anorexia nervosa are deficient in vitamin A. Requirement for this vitamin is increased in patients with appendectomy, burns, cirrhosis, and biliary obstruction. Stress can increase excretion. Zinc and protein deficiency can decrease transport. Premature infants and those suffering from cystic fibrosis and rheumatic fever are also at risk.
Signs and Symptoms of Deficiency: Night blindness is the earliest symptom.Severe vitamin A deficiency leads to xerophthalmia, which can result in corneal ulceration, Bitot’s spots, and blindness. Thickening of the bone, loss of lung elasticity, epithelial keratinization, impaired hearing, urinary calculi, and keratinization of salivary glands are also seen. In males, sperm production ceases. In females, fetuses are reabsorbed.
The hazards of excess vitamin A are well established with ingestion of excessive amounts of preformed vitamin A. Intake of 7,500-15,000 mg preformed retinal equivalents (RE) daily for periods of months to years can produce adverse effects including liver toxicity and possible birth defects. Prolonged daily consumption of <7,500 RE (<25,000 IU) is considered safe in the age group of 18-54. For the liver, it had to be taken for 6 years to become toxic. There has been one report of toxicity for doses in ranges as low as 1,500 – 3,000 mgm (5000-10,000IU), but these results were not reproducible and are contrary to the vast majority of the medical literature. There is no evidence that supplements of 3,000 mg RE (10,000 IU) are harmful to normal adults, including pregnant women and the elderly.
There is no evidence that conversion of beta-carotene to vitamin A contributes to vitamin A toxicity, even when beta-carotene is ingested in large amounts. The only consistent adverse effect of high beta-carotene intakes has been coloration of the skin related to hypercarotenemia. The possibility that beta-carotene causes lung cancer will be discussed later. A review of all published evidence on beta-carotene shows two studies, the ATBC trial and the CARET which suggest adverse effects. The rest of the evidence has shown beta-carotene to be safe.
Hypervitaminosis: Early signs of chronic hypervitaminosis are reflected in the skin, which becomes dry and pruritic, the liver, which becomes enlarged and cirrhotic, and in the nervous system, where a rise in intracranial tension mimics the symptoms of a brain tumor. Hypervitaminosis in pregnancy may cause congenital malformations like precocious skeletal growth and transient hydrocephalus. Anorexia, vomiting, loss of hair, nystagmus, gingivitis, glossitis, lymph node enlargement, and delayed clotting time are other symptoms. Isotretinoin is teratogenic and is absolutely contra-indicated in women with childbearing potential unless they have unresponsive, disfiguring acne. Hyperlipidemia occurs with prolonged use of isotretinoin. Hypervitaminosis can lead to vitamin neurotoxic effects. Closely related to the neurological symptoms of hypervitaminosis are symptoms including headache, pseudotumor cerebri, and embryotoxic effects reported in patients given vitamin A analogs or retinoids. Because vitamin A and analogs enter the CNS better than most vitamins, and because retinoids have many effects on enzyme activity and gene expression, Vitamin A neurotoxicity is more likely than all other vitamins. Megadose vitamin therapy may cause injury that is confused with disease symptoms. A study showed that after 49 months of follow up, ingestion of retinol caused a 7% increase in alkaline phosphatase, 11% increase in triacylglycerol, 3% increase in cholesterol and 1% decrease in HDL. The participants were randomly assigned to receive retinol (7,576 retinol equivalents RE, or 25,000 IU) or a placebo daily. Because a 1% increase in cholesterol concentrations has been reported to be associated with a 2% increase in coronary artery disease risk, long term ingestion of 7,576 RE vitamin A should be considered with caution.
Consuming too much vitamin A could increase your risk of osteoporosis. Two studies showed that a daily vitamin A intake > 1.5 mg resulted in a 6% decrease in overall bone density and doubled the risk of hip fracture. Excess levels of this vitamin weaken bones by increasing its rate of resorption.
Vitamin A is essential for normal reproduction and development. Doses > 10,000 IU/d as supplements have been reported to cause malformations in a single epidemiologic study. Nonhuman primate data show no teratogenicity at doses of 30,000 IU/d. Because no study reports adverse effects of 10,000 IU/d preformed vitamin A supplements, and this dose is more than the Recommended Dietary Allowance during pregnancy (2670 IU or 800 RE/d), it is recommend that women living in industrialized countries or who otherwise have nutritionally adequate diets may not need to ingest more than the RDA of preformed vitamin A as supplements. If periconceptional vitamin A exposures to levels up to 30,000 IU/d (9,000 μg RE/d) do occur unintentionally, multiple animal studies do support only very low risk. Teratogenicity nor vitamin A toxicity has been observed in multiple species exposed to high doses of beta-carotene.
Elderly people who take vitamin A may be at increased risk for vitamin A overload. Greater fasting plasma retinyl esters were associated with long-term vitamin A supplement use (>5y) and biochemical evidence of liver damage. For supplemental vitamin intakes of 5,001-10,000 IU/d, elderly people showed a 2.5 fold increase in plasma retinyl esters over non-users, while there was a 1.5 fold increase for young adults.
Isozymes of alcohol and other dehydrogenases convert ethanol and retinol to their corresponding aldehydes in vitro. New pathways of retinol metabolism have been described in hepatic microsomes that involve, in part, cytochrome P450s. In view of these overlapping metabolic pathways, it is not surprising that multiple interactions between retinol, ethanol, and other drugs occur. Accordingly, prolonged use of alcohol, drugs, or both results not only in decreased dietary intake of retinoids and carotenoids, but also accelerates the breakdown of retinol through cross-induction of degradative enzymes. Depletion ensues with hepatic and extrahepatic pathology, including carcinogenesis and contribution to fetal defects. Correction of deficiency through vitamin A supplementation is recommended. It is complicated by the intrinsic hepatotoxicity of retinol, which is potentiated by concomitant alcohol consumption. Beta-carotene was considered innocuous until recently, when it was found to also interact with ethanol.The combination of beta-carotene with ethanol results in hepatotoxicity. Moreover, in smokers who also consume alcohol, beta-carotene supplementation promotes pulmonary cancer and possibly, cardiovascular complications. Thus, ethanol, while promoting a deficiency of vitamin A, also enhances its toxicity as well as that of beta-carotene. In drinkers this narrowing of the therapeutic window for retinol and beta-carotene must be taken into account when formulating treatments aimed at correcting vitamin A deficiency.
Vitamin A, as retinol or retinyl esters is used to treat deficient patients. The RDA for vitamin A is 1.0 mg of retinol or its equivalent. The international unit (IU) is used to compare the biological activities of various sources of vitamin A.
James Goodwin presents the case for carotenoids and cancer. He makes the argument that the most consistent relationship between antioxidants and cancer has been made for carotenoids to lung cancer risk. Studies have found an inverse association of lung cancer risk with the frequency of consumption of dark green and yellow vegetables. One study showed a significant decrease in the risk of lung cancer (especially squamous cell carcinoma) with higher intake of total vitamin A, especially from vegetable sources. In the Western Electric Study, the protective effect of carotenoids was found in men at all levels of cigarette smoking. A seven-fold risk of developing lung cancer was observed for those in the lowest quartile of carotene intake at baseline.
Some studies have been inconsistent about smoking status and the protective effect of beta-carotene on lung cancer. A study of supplementation with antioxidants, the ATBC Cancer Prevention study, found significantly more lung cancer cases in the smoking group receiving beta-carotene supplements. This was also found to be the case in the CARET trial of asbestos workers. They were using 20 mg/day and 30 mg/day in the ATBC and CARET trials respectively. On the other hand, there was evidence in the CARET that beta-carotene may reduce the risk of lung cancer in former smokers. In contrast to these trials, no increased risk was noted in the longer term PHS trial.
The effects of alcohol or high intakes of retinal on the liver have been proposed as explanations for the adverse findings in the CARET and ATBC trials. Data suggests that heavy concurrent smoking is a necessary condition for a promotional effect of beta-carotene. Former smokers whose tissues would theoretically have been subjected to the some mutagenic and carcinogenic effects of cigarette smoke show decreased, not increased, rates of lung cancer with beta-carotene treatment.
Studies have also been done that suggest a positive role of carotenoids for breast, esophageal, cervical, pancreatic, and colorectal cancer. In another study, people with low vitamin A intake who received vitamin A had approximately a 50% reduction in their risk of breast cancer, providing evidence for a protective effect due to vitamin A itself. Carotenoid consumption also appeared to decrease risk of bladder cancer for those < 65. A nutrition study conducted in Linxian, China, showed that supplementation with retinol and zinc might protect against the development of gastric neoplasia.
Two trials have looked at supplementation with Cis-retinoic acid which prevented squamous cell carcinoma of the head and neck in smokers, and beta-carotene which reversed the changes of oral leukoplakia.[28,29]Beta-carotene had an inverse relationship with the development of thyroid carcinoma.
Beta-carotene supplementation for 2 years produces neither benefit nor detriment in the prevention of cardiovascular disease or cancer in women. The authors explain that individuals with high intakes of fruits and vegetables containing beta-carotene experience lower risks of developing cancer.
Dr. Dutta reported that Barrett’s esophagus patients who take beta-carotene supplements apparently experience improvements that appear to be due to a hike in a protective protein called heat shock protein (HSP-70). In earlier studies, Dr. Dutta demonstrated that beta-carotene supplementation reduced the burning sensation that these patients experienced. Beta-carotene was also shown to inhibit cancer cells in vitro.
It was found that dietary carotenoids and long term vitamin C supplementation may decrease the risk of cataracts.
Lycopene occurs in tomatoes and tomato products. Protective effects of a lycopene-rich diet on some types of cancer were suggested. There are several mechanisms potentially underlying the protective effects of lycopene. Little is known about the metabolism of lycopene. Potentially biologically active oxidation products of lycopene have been identified in human plasma. Cooking is a factor in releasing the desirable antioxidants from tomatoes. Research in the field of nutrition and health has shown that monounsaturated oils such as olive oil or canola oil are most desirable in facilitating absorption of lycopene. A study showed that consumption of 70-75 mg/d of lycopene can increase plasma concentrations of lycopene necessary for enhancing human health.
It was concluded that the consumption of tomato products may reduce the susceptibility of lymphocyte DNA to oxidative damage.
Tomato-based foods may be beneficial regarding prostate cancer risk. Intake of lycopene was inversely associated with risk of prostate cancer and advanced prostate cancers. Some observational studies found no beneficial effect of lycopene on prostate cancer risk.
Studies showed a pattern of protection against all cancers. The beneficial effect of raw tomatoes in this population may be due to the fact that they constitute perhaps the most specific feature of the Mediterranean diet. Other animal studies have found beneficial effects of lycopene in lung neoplasia and bladder cancer.
Age-related macular degeneration:
Lycopene may be beneficial in age-related macular degeneration and cataracts
Diabetes Mellitus Type-2
Increased free radical activity and high lipid oxidation impair glucose disposal in the peripheral tissues and exacerbate diabetic complications. Because of its extended system of conjugated double bonds, beta-carotene can scavenge peroxyl radicals and exert strong antioxidant activity, suggesting a protective effect against the development of type 2 DM. Several studies show that increased intake of vegetables that are rich in carotenoids lowers risk of type 2 DM. Those assigned to a diet with more vegetables have a lower incidence of type 2 DM. It is possible that the reduction in risk with vegetables rich in carotenoids may be due not to their beta-carotene content rather than other nutrients in these foods. Supplementation with beta-carotene for an average of 12 years had no effect on the risk of type 2 DM. In a study of hemodialysis patients, risk of diabetes was inversely related to plasma beta-carotene concentration. In a study of serum beta-carotene and risk of type 2 DM, participants had a 55% lower risk of development of type 2 DM, but this association was greatly reduced after controlling for cardiovascular risk factors. Plasma levels of other carotenoids, such as lycopene and cryptoxanthin, also were found to be inversely related to glucose intolerance.
Plasma vitamin A levels in diabetics:
Patients affected by type 1 DM showed that plasma retinol is significantly decreased in younger insulin-dependent diabetic patients, while alpha-tocopherol is significantly altered in diabetic patients with nephropathy. Plasma retinal, or its ratio to cholesterol, were significantly and independently reduced in the younger subset of diabetics as compared to controls. In patients with type 2 DM showed similar results, while two other studies showed no evidence of deficiency of vitamin A in Type 2DM subjects.
Relation between dietary vitamin intake and resistance to insulin-mediated glucose disposal:
A study suggests that vitamin A intake is associated with enhanced insulin-mediated glucose disposal.
Beta-carotene supplementation had no significant impact upon melenoma risk in a trial. An overall 17% reduction in melanoma was observed among physicians randomized to 50 mg of beta-carotene, but was not statistically significant.
Nutritional Anemia in Pregnancy
Improvement in vitamin A status may contribute to the control of anemia in pregnancy. Vitamin A and iron supplementation was studied in anemic pregnant women. Maximum hemoglobin was achieved with both vitamin A and iron supplementation with one-third of the response attributable to vitamin A and two-thirds to iron. After supplementation, the proportion of women who became non-anemic was 35% in the vitamin-A-supplemented group, 68% in the iron-supplemented group, 97% in the group supplemented with both, and 16% in the placebo group.
Trials showed that adequately supplying vitamin A, either through supplementation or adequate diet, had a major role in preventing morbidity and mortality in children in developing countries. In developed countries, vitamin A may also have a role in those with life threatening infections such as measles and those who may have a relative deficiency, such as premature infants.
Respiratory syncytial virus infection in children:
High dose vitamin A therapy is effective in reducing morbidity and mortality with measles infection. Children with acute respiratory syncytial virus (RSV) infection have low serum vitamin A concentrations. A trial of high dose vitamin A therapy among children 1 month to 6 years of age found no evidence of a beneficial effect of vitamin A for the treatment of RSV infection. One study showed that treatment of previously healthy respiratory syncytial virus-infected infants at doses of 12,500-25,000IU is safe and well tolerated.
Vitamin A therapy has been claimed to be of benefit to patients with Crohn’s disease. In one long-term study, vitamin A has shown no benefit to patients with Crohn’s disease who are in remission.
Summary Vitamin A and Carotenoids:
Vitamin A is essential for the support of the differentiation of epithelial cells and thus, maintains lung and tracheal integrity support and viability of the reproductive system and utilization in visual cycle. These three functions of vitamin A can be supported by dietary retinyl esters, retinal and retinal, but not retinoic acid. Vitamin A also stimulates immunity and is also essential for the formation of bone, protein, and growth hormone. Beta-carotene, the pre-vitamin form of vitamin A, acts as an antioxidant and also may enhance immune system functioning. Other members of the antioxidant carotene family include cryptoxanthine, a-carotene, zeaxanthin, lutein, and lycopene, most of which do not convert into significant amounts of vitamin A.
A number of claims have been made about the beneficial effects of vitamin A and the carotenoids, which includes: Night blindness; Retinopathy; Photosensitivity; Conjunctivitis and blepharitis; Macular degeneration; Cataract; Most infections; Urinary tract infection; Recurrent ear infection; Immune function; Minor injuries; Measles; HIV support; Crohn’s disease; Menorrhagia; Premenstrual syndrome; Abnormal pap smear; Peptic ulcer; Acne; and Alcohol withdrawal.
Night blindness is the earliest symptom of vitamin A deficiency, and vitamin A supplementation at this stage can help prevent development of xerophalmia, corneal ulceration, and blindness. Evidence exists in support of intake of vitamin A and carotenoids and decreased risk of cataracts. Vitamin A may prevent loss of lung elasticity, epithelial keratinization, salivary gland keratinization, urinary calculi, and impaired hearing. Dermatological problems like acne, psoriasis, Darier’s disease, and skin aging may also be treated effectively with retinoic acid and topical tretinoin. Improvement in vitamin A status may contribute to the control of anemia in pregnant women.
Evidence strongly suggests that higher intake of vitamin A, may significantly decrease the risk of lung cancer, especially squamous cell carcinoma. Low serum carotenoids were also found to be associated with a 200% increase risk of lung cancer. Studies suggest a positive role of carotenoids for breast, cervical, esophageal, pancreatic, and colorectal cancer. Vitamin A has shown a protective effect in the risk of breast cancer and may protect against the development of gastric neoplasia and squamous cell carcinoma of the head and neck. Carotenoid consumption has shown to decrease the risk of bladder cancer, and lycopene may reduce the susceptibility of lymphocyte DNA to oxidative damage. Supplementation with beta-carotene has shown inverse relationship with the development of thyroid cancer and also caused reversal of oral leukoplakia. Beta-carotene may also have a protective effect against the development of type 2 DM. A non-significant reduction in melanoma was observed with beta-carotene supplementation.
Populations who are prone to be deficient in this vitamin like patients with chronic intestinal diarrhea, malignancy, malaria, pneumonia, and anorexia nervosa should receive supplementation. As stress can increase the vitamin excretion, patients with appendectomy, burns, cirrhosis, and biliary obstruction may benefit from supplementation. Premature infants and those suffering from cystic fibrosis and rheumatic fever should receive vitamin A supplements.
Our recommendations for adults is 5000 IU/d of vitamin A with 100% beta-carotene. This amount can be obtained from approximately ¾ serving of boiled spinach, 2 ½ servings of raw carrots, 5 servings of raw papaya, and 1/5 serving of baked sweet potato. In general, a dose of <25000 IU is considered safe in the age group of 18-54. Beta-carotene is safe even when consumed in large amounts, and there is no evidence that conversion of beta-carotene to vitamin A contributes to vitamin A toxicity.
Vitamin A in excess is hepatotoxic and neurotoxic. In pregnant woman, it may cause congenital malformations in developing fetus, like precocious skeletal development and transient hydrocephalus. Long-term ingestion may increase cholesterol concentrations and thus, increase the risk of coronary artery disease and should be considered with caution. Risk of osteoporosis and hip fractures is also increased with excess consumption.