Michele M Gottschlich


Introduction 150

Vitamin A 150

General Metabolism 150

Role in Wound Healing 151

Consequences of Nutrient Deficiency 151

Consequences of Nutrient Excess 151

Recommendations to Optimize Wound Healing 156

Vitamin D 156

General Metabolism 156

Role in Wound Healing 156

Consequences of Nutrient Deficiency 157

Consequences of Nutrient Excess 157

Recommendations to Optimize Wound Healing 158

Vitamin E 158

General Metabolism 158

Role in Wound Healing 159

Consequences of Nutrient Deficiency 160

Consequences of Nutrient Excess 160

Recommendations to Optimize Wound Healing 160

Vitamin K 160

General Metabolism 160

Role in Wound Healing 161

Consequences of Nutrient Deficiency 161

Consequences of Nutrient Excess 161

Recommendations to Optimize Wound Healing 161

Future Directions 162

References 162


The functions, uses, and salutary effects of fat-soluble vitamins in wound healing are described in this review. This encompasses supplementation options for a spectrum of conditions of repair from the treatment of dermatologic disorders to more serious wound conditions. Guidelines are presented for intake of vitamins A, D, E, and K in an effort to optimize wound healing. Adverse events (primarily associated with vitamin E) as well as the consequences of fat-soluble vitamin toxicity are discussed.

vitamin a

General Metabolism

The term "vitamin A" is often employed generically for derivatives such as retinol, retinal, retinoic acid, and retinyl. It is acquired from the diet either as preformed vitamin A or as its provitamin A carotenoids. The term "provitamin A" is used to describe all carotenoids that show the biological activity of vitamin A. Of the ten forms of carotenoids, the most significant is beta-carotene. In mammals, P-carotene-15,15-dioxygenase catalyzes conversion of beta-carotene to retinal. This initial cleavage enzyme is rate limiting and noninducible. Beta-carotene's biologic activity is about one-sixth that of preformed vitamin A — making it less toxic. Dietary sources of vitamin A are summarized in Table 9.1.

After foods are ingested, preformed vitamin A of animal tissues and the provitamin carotenoids of vegetables and fruits are released from proteins by the action of proteolytic enzymes, first collecting in the stomach as fatty globules and then entering the duodenum. In the presence of bile salts, the globules are broken down into smaller lipid moieties that are further digested by pancreatic lipase and hydro-lases. The resultant micelles are then readily absorbed into mucosal cells, mainly in the upper portion of the intestine. Under normal conditions, over 90% of vitamin A is stored in the liver.

The best elucidated role of vitamin A is in the visual process, where it is converted into the photopigments of rod and cone cells of the retina. Visual function is mediated by retinal, exclusively.

Although less well understood, the extra-retinal functions of vitamin A are of greater physiological impact than the visual function. Collectively referred to as "systemic" functions of the vitamin, this includes vital roles in differentiation, proliferation, and function of epithelial cells and on growth in general. That vitamin A plays a major role in epithelialization throughout the body (1), and that vitamin A deficiency has a detrimental effect on wound healing (2) has been known for many years.

Vitamin A also supports immunocompetence. Vitamin A deficient animals and humans are typically more susceptible to infection and have higher mortality rates than individuals with adequate vitamin A nutriture. Retinoids and carotenoids appear to affect immunity in different ways. Retinoids act on the differentiation of immune cells, increasing the number and nature of white blood cells and increasing phagocytosis of monocytes and macrophages involved in immune, inflammatory, and wound healing processes (3,4). Carotenoids seem to affect immunosurveilance of activated natural killer (NK) cells and T-helper cells by modifying the release of at least some cytokine-like products by activated lymphocytes and monocytes.

Role in Wound Healing

Vitamin A has been effectively used pharmacologically in numerous inflammatory and dermatologic diseases, such as acne, atopic dermatitis, photodamage, striae, cellulite, and disorders of keratinization, including psoriasis and corneal healing (5-12). Pretreatment with retinoids before epidermal injury accelerates repair following cosmetic procedures such as chemical peels and dermabrasion (9,13-15).

Numerous studies have demonstrated the positive role of vitamin A in the treatment of open wounds. Known processes that influence healing that require vitamin A include epithelial growth, synthesis of glycoproteins and proteoglycans, cellular immunity, and the inflammatory reaction (3,4,7,16-20). Vitamin A can reverse the anti-inflammatory effect of steroids on wound healing. Reports by Hunt and colleagues (21-25) and others (26) have repeatedly shown that local or systemic administration of vitamin A to a steroid-retarded wound accelerates the formation of healthy granulation tissue and the healing rate. Vitamin A supplementation also increases collagen content and breaking strength in a variety of experimental models, including cutaneous wounds, flexor tendon repair, and intestinal anastomoses, to name a few (16,17,24,27-30). In vitro, vitamin A can accelerate fibroblast maturation and multiplication and increase the number of fibroblast receptors for epidermal growth factor (16,30). Additionally, both topical and enteral supplementation with this vitamin have been shown to facilitate wound healing in laboratory animals (3,17,18,26-28,31-36), as well as in the clinical repair (37,38) of wounds associated with fractures, burns, ulcerations, radiation, and antineoplastic therapies, or strepto-zotocin-induced diabetes.

Consequences of Nutrient Deficiency

Table 9.1 highlights those at high risk of inadequate vitamin A status. Vitamin A deficient individuals experience replacement of normal mucous-secreting cells by cells that produce keratin (1), particularly in the conjunctiva and cornea, the trachea, the skin, and other ectodermal tissues. Deficiency symptoms include xerophthalmia (night blindness, conjunctival xerosis, Bitot's spots), respiratory ailments (pneumonia, bronchopulmonary dysplasia), increased susceptibility to infection, stunted growth, skin disorders, and delayed wound healing (21,39,40). Vitamin A deficiency impairs epithelialization, collagen synthesis, wound contraction, and cross-linking of newly formed collagen.

Consequences of Nutrient Excess

Short-term vitamin A supplementation with large amounts (150,000 IU) has not resulted in adverse side effects (3). However, prolonged high doses of vitamin A (over 50,000 IU/d) can be toxic (41). Clinical symptoms include nausea, vomiting, headache, dizziness, muscle weakness, gingivitis, alopecia, and peeling skin. An excessive inflammatory response, defects in cell-mediated immunity, visual and liver

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