The Nutritional Relationships of A

David L. Watts, Ph.D., F.A.C.E.P.1

Introduction , the first fat-soluble vitamin to be Roughness of the skin occurs due to recognized, has been described as one of the most hyperkeratosis of the hair follicles. During versatile due to its many roles in body development, a deficiency of vitamin A leads to functions. The most well-defined function of abnormalities in dentine formation and bone vitamin A is its role in vision. It is also involved growth. in maintenance and integrity of the mucous mem- Causes of vitamin A deficiency include branes, skin, remodeling, and growth of bones. inadequate intake, impaired absorption or Other roles include maintaining the stability of storage, and poor conversion of carotene to active cell membranes and nerve sheaths, synthesis of vitamin A. Poor absorption and/ or storage is adrenal cortical hormones (corticosterone), and associated with excessive intake, celiac regulation of thyroxin output. Vitamin A is also disease, cystic fibrosis of the pancreas, ulcerative involved in the manufacture of red blood cells colitis, biliary obstruction, and cirrhosis of the and assists the immune reaction. More recently .4 researchers have suspected that vitamin A is involved in cellular differentiation and gene A expression. Over the past 10 years vitamin A has of vitamin A occurs with protracted been investigated for the prevention and treat- high doses. has been observed ment of various types of cancers.1 2 3 following the consumption of liver, which contains 20,000 LU. per gram.5 Vitamin A Requirements Symptoms of vitamin A toxicity include joint The terminology for the measurement of pain, decalcification, and fragility of bone. vitamin A is presently in transition. This is due to Increased produces pseudo the various forms of the pre-vitamin, which are brain tumor symptoms. Red blood cells lose converted into the active form () at hemoglobin, and bleeding can occur easily. different efficiencies. Therefore the term retinol symptoms include irritability, equivalents (R.E.) is beginning to replace restlessness, fatigue, anorexia, and muscle international units (LU.). RE is the amount of weakness. Rashes may develop on the skin, retinol a vitamin A compound will yield causing dryness and peeling along with hair loss. following conversion by the body. The lips may also become scaly. The spleen and Recommended dietary allowances for infants and liver enlarge and jaundice may develop.6 children are 420-700 RE, males 1,000 RE, Symptoms of toxicity subside with reduced females 800 RE. During and lactation, intake of the vitamin. the RDA is increased 200 and 400 RE respectively. Larger doses of short duration are Vitamins Synergistic to Vitamin A required when deficiency symptoms exist. As with minerals, rarely does a develop singularly. Synergistic co- Hypovitaminosis A factors should also be taken into consideration The most recognized early sign of vitamin A when determining vitamin A requirements and deficiency is night blindness (impaired night during therapy. vision), xeropthalmia, and Bitot's spots. is considered synergistic to vitamin A due to its antioxidant activity, which results in 1. Trace Elements, Inc., P.O. Box 514, Addison, Texas a sparing effect upon vitamin A.7 Vitamin E also 75001. aids in stabilization of cell membranes. Loss of vitamin A from liver stores is accelerated in the 27 Journal of Orthomolecular Medicine Vol. 6, No. 1, 1991 presence of vitamin E deficiency as a result of Other vitamins having a potential to antagonize 8 increased fragility of lysosomal membranes. vitamin A include B1, B12, B6, and K. Their Vitamin C is also thought to act as an mechanisms of action are not completely antioxidant for hepatic vitamin A stores. Animal understood but probably adversely affect vitamin studies have shown that vitamin A has an A when stores or intakes are extremely low. They influence on the hepatic synthesis of ascorbic can also increase vitamin A utilization. acid.9 Any nutrient having antioxidant activity can be considered synergistic to vitamin A. Minerals Synergistic to Vitamin A Because of its synergistic effect upon the The zinc is intimately associated with mineral zinc, vitamin B6 can be considered vitamin A. Adequate amounts are required for the synergistic to vitamin A.10 Zinc is, of course, mobilization of vitamin A from the liver. In involved in the regulation of vitamin A.11 several experiments involving animal and human The B complex in general has been associated studies, vitamin A deficiency symptoms did not with vitamin A activity. Besides B6, vitamin B1, respond to vitamin A supplementation alone

B2B , B3, and B5 have been specifically described as when a zinc deficiency co-existed. However vitamin A synergists.12 symptoms of vitamin A deficiency, such as impaired night vision, improved only after zinc Vitamins Antagonistic to Vitamin A supplementation. Zinc is involved in maintaining Figure 1 indicates the vitamins that are the plasma binding protein (RBP),a considered to be antagonistic to vitamin A. specific transporter for vitamin A.18 Vitamin A may also be considered antagonistic to Iron deficiency anemia is associated with low these vitamins. vitamin A status as well as reduced hemoglobin Vitamins D and A are often considered levels.19 Vitamin A apparently facilitates the synergists and, in a supplement form, are mobilization of stored iron for incorporation into frequently given in combination. However, erythrocytes.20 vitamin A can be given to reduce the toxic effects is involved in antioxidant activity of hypervitaminosis D.13 In general the fat soluble and therefore can be considered synergistic to vitamins compete for absorption and transport; vitamin A. Both vitamin A and selenium have therefore, the entire fat soluble family can be similar effects upon inhibiting carcinogenesis.21 considered antagonistic.14 The different effects on Other minerals synergistic to vitamin A bone metabolism also indicate vitamin A and D include magnesium, manganese, potassium, and antagonism. Vitamin D increases the absorption . Like vitamin A, these minerals are and retention of calcium, while excess vitamin A closely related to thyroid function.22 causes and decalcification. Being oil soluble, vitamin E may compete with Minerals Antagonistic to Vitamin A vitamin A for absorption. Vitamin A is known to Figure 2 shows the minerals that are suppress vitamin E levels in immunopoietic considered antagonistic to vitamin A. Vitamin A tissue.15 may also be mutually antagonistic to these The antagonistic effects are also indicated by elements. the opposite effects of vitamins A and E on Excessive tissue iron accumulation may prostaglandin E1 and E2 (PGE2 PGE2) synthesis. increase vitamin A requirements due to 16 Vitamin E suppresses PGE2 and enhances PGE1 destruction by peroxidation. Excess iron synthesis, while vitamin A enhances PGE2 accumulation can occur due to a severe copper synthesis. High levels of vitamin E intake may deficiency.23 also interfere with beta carotene absorption.17 Even though selenium is an antioxidant, under Due to its copper lowering effect, vitamin C certain circumstances and in large amounts, it can may contribute to the oxidation of vitamin A by act as a pro-oxidant, resulting in adverse effects increasing tissue iron accumulation. on the fat

28 The Nutritional Relationships of Vitamin A

soluble vitamins.24 Iodine in the form of T4, although synergistic to vitamin A, is antagonistic as well.25 Adrenal Hormones and Vitamin A The minerals copper, calcium, and sodium can The adrenocortical hormones increase the have an indirect antagonistic effect upon vitamin mobilization of vitamin A from the liver. This A due to their interrelationship with the thyroid effect has also been reported in the treatment of 33 gland.26 27 rheumatic children with cortisone. Adequate Any factor that antagonizes the mineral zinc adrenal function is also necessary for the can be a potential antagonist to vitamin A, e.g., mobilization of vitamin A stores. It is possible cadmium and mercury. that adrenal and thyroid insufficiency contributes to signs of vitamin A deficiency or increased Endocrine Relationship to Vitamin A requirements due to an inability to mobilize it As with minerals, vitamins are also affected by from storage. endocrine activity. Hormone levels can directly affect vitamin A status and requirements. Protein Thyroid and Vitamin A Adequate protein is necessary for the The conversion of carotene to vitamin A is mobilization of vitamin A from the liver to the influenced by thyroxine. Studies show that blood stream. Vitamin A deficiency is associated thyroidectomy or suppression of the thyroid with protein malnutrition. Normal serum vitamin produces hypercarotenemia and reduced retinol A levels can be restored when protein is added to levels in the liver.28 29 It has been speculated that the , providing there are adequate liver vitamin A deficiency is associated with reserves of the vitamin. However, if liver reserves hypothyroidism. Studies reveal that low vitamin of vitamin A are depleted, dietary protein may A levels are associated with goiter formation.30 precipitate an acute vitamin A deficiency.34 Overactivity of the parathyroid due to its suppressing effect upon the thyroid and its Assessment of Vitamin A Status relationship with vitamin D may also increase Over 90% of the vitamin A reserves are in the vitamin A requirements.31 liver; therefore, serum levels do not truly reflect vitamin A status. The serum levels however do Estrogen and Vitamin A reflect a deficiency when liver reserves are Tissue estrogen sensitivity is increased in the depleted and an excess when liver stores are over presence of vitamin A deficiency.32 The saturated.35 concentrations of RBP are lowest prior to the preovulatory peak in estradiol levels. According Conclusion to the study reported by Keyvani, et al, females As with other nutrients, requirements for are affected by goiter more than males due to the vitamin A should be assessed in conjunction with fact that females have lower vitamin A levels. its co-factors. Nutritional therapeutics involving

29 Journal of Orthomolecular Medicine Vol. 6, No. 1, 1991

vitamin A may be greatly enhanced when the Suppresses Prostaglandin E2 Synthesis synergists and antagonists are taken into and Enhances The Immune Response of Aged consideration. Since vitamin A is closely related Mice. Mechanisms of Aging and Dev. 34, 1986. to the thyroid gland, it can be speculated that 17. Machlin LJ: Use and Safety of Vitamin E in subclinical deficiencies are related to hypo- Adults. In: Elevated Dosages of Vitamins. Walter, P., Stahelin, H., Brubacher, G. thyroid conditions. Some of the more common (eds.), Hans Huber Pub., N.Y., 1989. symptoms associated with hypothyroidism that 18. Smith JC: Interrelationship of Zinc and Vitamin A may respond to vitamin A include Metabolism in Animal and : A hyperlipidemia, atherosclerosis, adult onset Review. In: Clinical, Biochemcial and Nutritional diabetes, fatigue, depression, cold sensitivity, Aspects of Trace Elements. Prasad, A.S. (ed.), Alan changes in skin and hair texture, and anemia. R. Liss, N.Y., 1982. 19. Bozorghmehr B, Ghaemi M: A Study of Possible Relationship Between Vitamin A and Some References Hematopoietic Factors. Am. J. Clin. Nutr. 46, 3, 1. Greenwald MD, Ershow AG, Novelli WD, Benton 1987. C (eds.): Cancer, Diet, and Nutrition: A 20. Meja LA, Hodges RE, Rucker RB: Am. J. Clin. Comprehensive Source Book. Marquid Pub. 111., Nutr. 32, 1979. 1985. 21. Clement I: Susceptibility of Mammary Car- 2. Prasad KN: Vitamins, Nutrition and Cancer. cinogenesis in Response to Dietary Selenium KragerPub. N.Y., 1984. Levels: Modification by Fat and Vitamin Intake. 3. Meyskens FL, Prasad KN (eds.): Modulation and In: Selenium in Biology and Medicine, Part B. Mediation of Cancer by Vitamins. Krager Pub. Coombs, G.F., Spallholz, J.E., Levander, O.A., N.Y., 1983. Oldfield, J.E. (eds.), Van Norstrand Reinhold Co., 4. Goodhart, Wohl (eds.): Modern Nutrition in N.Y., 1987. Health and Disease, 3rd Ed. Lea and Febiger, 22. Watts DL: The Nutritional Relationships of the Phil., 1964. Thyroid. /. Orthomol. Med. 4,3,1989. 5. Pease CN: J.A.M.A. 182, 1962. 23. Watts DL: The Nutritional Relationships of Iron. /. 6. Whitney EN, Cataldo CB: Understanding Normal Orthomol. Med. 3,3, 1988. and Clinical Nutrition. West Pub., St. Paul, MN, 24. Heiby WA: The Reverse Effect. MediScience Pub., 1983. 111., 1988. 7. Bauernfiend JC, Newmark H, Brin M: Vitamin A 25. Kutsky RJ: Handbook of Vitamins, Minerals and and Nutrition Via Intramuscular or Oral Route. Hormones, 2nd Ed., Van Norstrand Reinhold Co., Am. J. Clin. Nutr. 27, 1974. N.Y., 1981. 8. Roels OA, Trout M, Guha A: Biochem. J. 97 1965 26. Watts DL: The Nutritional Relationships of 9. Eliot JG, Lachance PA: /. Nutr., 110, 1980. Copper. /. Orthomol. Med. 4,2, 1989. 10. Aboaysha AM, Kratzer FH, Sifri M: Vitamin B-6 27. Watts DL: The Nutritional Relationships of Plasma Amino Acids and Liver Zinc Calcium. /. Orthomol. Med. 5,2, 1990. Interrelationships. Poultry Sci. 55, 1976. 28. Moore T: Vitamin A. Elsevier, N.Y., 1957. 11. Solomons NW, Russell RM: The Interactions of 29. The Vitamins. Am. Med. Assoc., Chicago, 1939. Vitamin A and Zinc: Implications for Human 30. Keyvani F, et al: Vitamin A Status and Endemic Nutrition. Am. J. Clin. Ntur. 33, 1980. Goiter. Am. J. Clin. Nutr. 46, 3, 1987. 12. Kutsky RJ: Handbook of Vitamins, Minerals and 31. Watts DL: Indications of Parathyroid Activity in Hormones, 2nd Ed. Van Norstrand Reinhold Co., Hair Tissue Mineral Patterns. T.L.F.D. Oct. 1989. N.Y., 1981. 32. White, Handler, Smith: Principles of Biochemistry, 13. Clark and Basset:/. Exp. Med. 115, 1962. 3rd Ed., Mcgraw Hill, 1964. 14. McDowell LR: Vitamins in Animal Nutrition, 33. Sporn MB, Roberts AB, Goodman DS (eds.): The Comparative Aspects to Human Nutrition. , Vol. 1. Academic Press, N.Y., 1984. Academic Press, N.Y., 1989. 34. Roels OA, Lui NST: The Vitamins, Vitamin A and 15. Tengerdy RP, Mathias MM, Nockels CF: Vitamin Carotene. In: Modern Nutrition in Health and E, Immunity and Disease Resistance. In: Diet and Disease, 5th Ed. Goodhart, R.S., Shiles, M.E. Resistance to Disease, Advances in Experimental (eds.), Lea and Febiger, Phil., 1973. Medicine and Biology, Vol. 135. Phillips, M., 35. Sporn MB, Roberts AB, Goodman DS: The Baetz, A. (eds.), Plenum Pub., N.Y., 1981. Retinoids, Vol. 1. Academic Press, N.Y., 1984. 16. Meydani S, et al: Vitamin E Supplementation

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