tn disturbances, coma, and connective tissue disorders can also result from excessive vitamin A (21,41-44). Signs of vitamin A intoxication are usually reversed upon cessation of exposure.
Proper wound healing depends upon adequate, and in some situations, augmented vitamin A status of the host. Any deficiency of existing vitamin A deficiency should be corrected as soon as possible so that wound healing may progress at an appropriate rate.
Although vitamin A has thus far yielded promising results for the treatment of wounds, research-based guidelines for the pharmacologic modulation of wound healing cannot be made at present. There are surprisingly few clinical outcome studies that examine optimal dosage. Nevertheless, it has been recommended that 1000 IU/d be administered to malnourished individuals before and after elective surgery (45). In addition, experts suggested supplementation from 10,000 to 25,000 IU of vitamin A per day in patients with severe injuries, burns, and gastrointestinal dysfunction, and those with fractures or tendon repairs and those being treated with high-dose radiation therapy or steroids (16,37,39,46-48). The strength of these recommendations is unclear, and further investigation is required.
Two principal forms exist: cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2). Vitamin D2 is obtained from the diet (Table 9.1), in which case it is absorbed, with the help of bile salts, in the small intestine. Vitamin D3 is produced endogenously by keratinocytes in the skin via biosynthesis from 7-dehydrocholesterol upon exposure to ultraviolet light. The epidermis is where the greatest amount of vitamin D production occurs (49). It is conceivable that large cutaneous wounds and scarring impair the process of epidermal vitamin D synthesis (50,51). Burn scar and normal skin adjacent to the wound show a fivefold decrease in the ability to transform 7-dehydrocholesterol to vitamin D3 (51).
As vitamin D enters the circulation, both vitamin D2 and vitamin D3 are biologically inert and must undergo hydroxylation to produce their biological responses. Vitamin D is hydroxylated sequentially in the liver and kidney, first to 25-hydroxyvitamin D (the major circulating form), and then to its most physiologically active form, 1,25-dihydroxyvitamin D. This conversion is regulated through concentrations of serum calcium, phosphorus, and parathyroid hormone. Vitamin D functions in a manner analogous to the steroid hormones. Important actions include its role in calcium and phosphorus absorption, calcium and phosphorus homeostasis, and endochondral bone formation (52).
Apart from the calciotropic tissues (e.g., bone, intestine, and kidney), recent research suggests a biological role for vitamin D in wound repair (53,54). It has been shown that vitamin D has the ability to regulate growth and differentiation of other cell types, including cancer cells, B and T lymphocytes, melanocytes, fibroblasts, endothelial cells, and monocyte/macrophages (55-61). Furthermore, 1,25-dihydroxyvita-min D3 reverses corticosteroid-induced epidermal atrophy (62) and promotes the differentiation and proliferation of normal epidermal keratinocytes (59,63-69). In contrast, inhibitory effects of 1,25-dihydroxyvitamin D3 on proliferation of hyperplastic epidermis occurs (52,70-72), possibly mediated through growth factors and cytokines (73). Pharmacologic amounts of 1,25-dihydroxyvitamin D3 has been used as an effective agent for inhibiting hyperproliferative diseases, such as psoriasis (52,71,72) and cancer (52,59,74-76).
Time course and specificity studies demonstrated that daily topical application of 1,25-dihydroxyvitamin D3 significantly accelerated healing of full thickness cutaneous wounds in rats at 1 to 5 d after wounding (54). Another study in rats demonstrated intraperitonial D3 to produce a significant increase in wound breaking strength and improved epithelialization (53).
1,25-Dihydroxyvitamin D3 has been shown to stimulate the synthesis of fibronec-tin, a prominent component of wound healing (77,78). Macrophages may also play an important role in the 1,25-dihydroxyvitamin D3 mediated wound healing process. It has been reported by Abe et al. (57) that 1,25-dihydroxyvitamin D3 activates the maturation of macrophages (cells actively involved in wound healing). Thus, vitamin D has numerous activities that affect the process of wound healing.
A deficiency of vitamin D results in inadequate intestinal absorption and renal reabsorption of calcium and phosphorus. As a consequence, serum calcium and phosphate concentrations drop, and serum alkaline phosphatase activity increases. In response to low serum calcium levels, hyperparathyroidism may occur. Vitamin D deficiency has been associated with adverse effects on the skeletal (50,79-87), neuromuscular (88,89), endocrine (47,90,91), and immune (58-61,92-94) systems. Clinical symptoms include growth arrest in children, low bone mineral density, increased fracture incidence, and impaired healing.
Vitamin D toxicity does not occur from prolonged exposure of the skin to ultraviolet (UV) light. Pharmacologic doses are also usually well tolerated (95,96). Few data from which to establish vitamin D safety and toxicity limits exist. Vieth and colleagues (97) and Heaney et al. (98) demonstrated that doses of 75-125 |g/kg daily are well tolerated in healthy adults. Gottschlich et al. (50) have shown this to also be the case while administering up to 100 |g/d in pediatric burn patients. However, toxicity may be of concern in those patients receiving prolonged treatment with supplemental vitamin D. For example, a few reports of overdosage and toxicity exist from extreme amounts (in the range of 250 | g/d for 4 months to 5000 | g of vitamin D daily for 2 weeks) (99-101). Intoxication is associated with elevated plasma 25-hydroxyvitamin D concentration (rather than high 1,25-dihydroxy vitamin D), causing hypercalcemia with attendant decreases in serum parathyroid hormone (PTH). Other symptoms include hypercalciuria, anorexia, nausea, vomiting, headache, diarrhea, thirst, polyuria, muscle weakness, fatigue, joint pain, demineralization of bones, pruritus, nervousness, disorientation, psychosis, and tremor. Hypervitaminosis D is a serious problem, because it can result in irreversible deposition of calcium and phosphorus in the heart, lungs, kidneys, and other soft tissues. Therefore, it is important to detect early signs of vitamin D toxicity. It is fortunate that serum 25-hydrox-yvitamin D is the best screen for both hypervitaminosis and hypovitaminosis D (102).
Those presenting with a heightened risk of hypovitaminosis D (Table 9.1) merit assessment of vitamin D status with therapeutic correction of low serum levels in an effort to minimize the adverse effects of classic deficiency symptoms (delayed growth and osteoporosis) as well as to address more recent findings demonstrating benefits of vitamin D as it pertains to the immune system and epithelial proliferation. In the future, 1,25-dihydroxy vitamin D3 may represent a new avenue in wound medication; however, more research is needed to define its clinical application in wound healing.
The term "vitamin E" refers to a group of at least eight compounds — a-, P-, y-, and S-tocopherols and a-, P-, y-, and S-tocotrienols. All eight isomers are widely distributed in nature. a-Tocopherol has the highest biological activity.
Table 9.1 lists food sources of vitamin E. Only 20 to 40% of orally ingested tocopherol or its esters are absorbed. Efficiency of absorption is enhanced by the presence of dietary lipids. Medium-chain triglycerides in particular enhance absorption, whereas polyunsaturated fatty acids are inhibitory. Both bile and pancreatic juice are necessary for maximal absorption of vitamin E.
Vitamin E is an antioxidant and free radical scavenger that helps prevent the oxidation of cell membranes, which is very important for their stability and structure (103-107). In this role, vitamin E is considered a significant line of defense against lipid peroxidation, offsetting oxidative damage that occurs with disease, injury, inflammation, and environmental insult (105,108-113).
Several other functions of vitamin E have been identified, which are likely not related to its antioxidant capacity (113,114). Vitamin E has a role in the immune response, inflammation, platelet aggregation, platelet adhesion, protein kinase C activation, lipoprotein transport, nucleic acid and protein metabolism, mitochondrial function, and hormonal production (104,114-118). Vitamin E spares selenium (a component of the enzyme glutathione peroxidase) and protects vitamin A from destruction in the body.
The role of vitamin E in the healing of wounds is controversial. In chronic wounds, necrotic tissue, bacteria, and ischemia trigger inflammatory cascades that enhance liberation of free radicals (119). Vitamin E may decrease damage to the wound induced by excessive free radical release. Vitamin E is also thought to facilitate wound healing by enhancing the immune response (115,116).
Lee (120) conducted the first controlled study of the effect of vitamin E on wound healing in humans. He described 57 patients who had been under care for stasis ulcers for at least 3 months. Lee found that 28 patients receiving vitamin E supplementation had improved frequency of healing and healing time as compared to 29 patients on placebo.
Researchers likewise reported some animal studies in which rats receiving oral vitamin E experienced accelerated wound healing. For example, Taren et al. (121) demonstrated increased breaking strength of wounds in rats pretreated with systemic vitamin E and then irradiated. In addition, oral and topical vitamin E has been shown to enhance wound closure and breaking strength in rats following burns and surgery (122,123).
Vitamin E has achieved an unusually prominent role in the mind of the lay public as being beneficial for healing and for the prevention of scar formation (124,125). However, it is prudent to note that many claims are anecdotal, and existing in the literature as well are scientific reports implicating vitamin E as a negative effector of the wound healing process. For example, Greenwald (29) found that vitamin E interfered with collagen synthesis and decreased tensile strength of wounds and impaired tendon healing in chickens. Ehrlich et al. (32) reported that microscopic sections from rats treated with a massive amount of vitamin E had the appearance of less collagen and cells, and demonstrated decreased breaking strength of the wounds, along with an inhibited inflammatory response and a reduction in the number of fibroblasts.
Antiproliferative effects of vitamin E (114) suggest that it might be beneficial in the clinical setting in preventing the development of keloids or hypertrophic scarring. Unfortunately, efforts to date using either topical or systemic vitamin E have not consistently demonstrated benefit, although only three controlled studies have been reported. One clinical trial found that vitamin E improved the effect of silicon bandages on the treatment of large, well-established keloid scars (126). Favorable results were not apparent when vitamin E was evaluated as a means of scar prevention. For example, Jenkins et al. (127) evaluated the topical use of vitamin E on acute scar formation, change in graft size, cosmetic appearance, and range of motion. In that study, 159 procedures involving reconstructive surgery were randomized to postoperative treatment for 4 months with topical steroid, topical vitamin E, or placebo. Neither topical steroid nor vitamin E was effective in reducing scar formation. Furthermore, 19.9% showed adverse reactions in the form of rash or itching, requiring discontinuation of the vitamin E. Likewise, Baumann and Spencer (124) showed that topically applied vitamin E did not improve scar appearance, and it led to a 33% incidence of contact dermatitis in patients who had undergone skin cancer removal surgery. Adverse follicular and papular dermatitis has also been associated with the use of vitamin E in cosmetics (128,129).
It is generally accepted that the prevalence of vitamin E deficiency in humans is rare. During conditions of vitamin E inadequacy, there is damage to many cells, particularly the red blood cells, T and B cells, and muscle and nerve cells (111,115,116,130,131). The various clinical signs of vitamin E deficiency are believed to be manifestations of membrane dysfunction resulting from the oxidative degradation of polyunsaturated membrane phospholipids or the disruption of other critical cellular processes. Deficiency symptoms include increased platelet aggregation, decreased red blood cell survival, hemolytic anemia, neurologic abnormalities (e.g., altered reflexes, gait disturbances, limb weakness, sensory loss in the arms or legs), and excessive creatinuria (132-134).
The toxicity of vitamin E is very low (95,135-137). There is no evidence of adverse effects from the consumption of vitamin E naturally occurring in foods. Side effects of a minor nature can occur from very high doses of vitamin E supplements (> 670 mg/d). Symptoms include headache, nausea, double vision, fatigue, dermatitis, and retarded wound repair. Intake of high levels can also exacerbate the blood coagulation defect of vitamin K deficiency (138) and antagonize the wound healing effects of vitamin A (32).
Purported beneficial effects have been widely variable. Certainly, correction of vitamin E deficiency is always warranted. The benefits of pharmacologic vitamin E, with the intent of modulating surgical wound healing and acute scar formation, have not been reliably demonstrated.
Conservative use of vitamin E supplements is recommended in lieu of the dubious effects of this vitamin on the healing process. Goodson and Hunt (139) report patients whose healing was retarded by doses of vitamin E over 1000 IU/d. Horwitt (132) recommends < 1000 mg as an upper limit for vitamin E. Certainly, high doses should be avoided until studies demonstrate the optimal route and level of vitamin E supplementation for wound repair.
Vitamin K exists naturally in two forms: as Kj or phylloquinone, and as K2 or menaquinone. Phylloquinone is found in plants. Green leafy vegetables constitute the major source of vitamin K in the diet. The second source of vitamin K is the menaquinones, which are synthesized by certain bacteria including intestinal microflora.
Under normal conditions, vitamin K is moderately well absorbed from the jejunum and ileum. As with other fat-soluble vitamins, absorption depends on a normal flow of bile and pancreatic secretions and is enhanced by dietary fat.
The metabolic role of vitamin K is to act as a cofactor for a microsomal enzyme (vitamin K dependent carboxylase) which promotes the modification of specific glutamic acid residues to carboxyglutamic acid (gla) in certain proteins referred to as being "vitamin K dependent." These gla-containing proteins are known to occur in a variety of tissues, such as kidney, placenta, pancreas, spleen, and lungs. Specific gla-proteins are required for thenormal function of blood clotting. As such, vitamin K is involved in the hepatic biosynthesis of factors II (prothrombin), VII (proconvertin), IX (antihemophilic factor B), and X (Stuart-Prower factor). In addition, a major protein of the bone matrix, osteocalcin, has also been found to be vitamin K dependent.
Vitamin K has no known direct role in the wound. The relevance of vitamin K to wound healing involves its function in coagulation, which is a prerequisite of healing. Optimal wound healing requires the prevention of hemorrhage and hematoma formation, which impair wound healing.
Vitamin K deficiency presents with clinical features ranging from mild bruising to life-threatening hemorrhage. Impaired coagulation can have a detrimental effect on wound healing, as bleeding disorders and wound hematomas predispose to infection and poor tissue repair.
The administration of supplements containing natural vitamin K is assumed to be safe and have neglible adverse effects. One case report suggestive of anaphylactoid toxicity exists in the literature (140). The actual prevalence of anaphylactoid reactions to vitamin K is believed to be rare, given the prevalence of use of intravenous vitamin K (141).
People at risk of vitamin K deficiency, particularly those expected to have prolonged periods of restricted food intake while requiring antibiotics, should be monitored and treated, because normal coagulation is required for optimal wound healing. The precise dose of supplemental vitamin K that high-risk patients should receive is unknown; however, amounts administered in the range of 5 to 10 mg (orally or intramuscularly) one to three times weekly are common (142,143).
Nutrition plays a significant role in the wound healing process. This chapter focused on the importance of the fat-soluble vitamins for tissue regeneration. Clinical experience and research have shown that deficiency of vitamins A, D, E, or K may be associated with impaired wound healing. Likewise, there exists suggestive evidence that pharmacologic therapy with each of the fat-soluble vitamins may be associated with enhanced wound repair, although the specific benefit and amount of supplementation in patients who are not clinically deficient remains controversial. Before pharmacologic use of these vitamins for wound therapy becomes routine, further research is clearly justified, as no vitamin reviewed here has been the subject of a large, double-blind clinical study.
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