The Potential Role of Specific Amino Acids, Vitamins, and Zinc Oral Supplementation as Support Strategies for the Management of Chronic Wound

  

    
Nutrient
    
Mechanism    of action
  
  

    
Arginine
    

      
Protein anabolism;
      
Cellular growth and proliferation;
      
Improve the production of nitric oxide (responsible for vasodilatation,    secretion of growth hormones and growth factors and immune response    mediator).
    
  
  

    
Glutamine
    

      
Cellular division (enterocytes and leukocytes);
      
Key role for the immune system.
    
  
  

    
HMB
    

      
Proteolysis inhibition and protein turnover modulation.
    
  
  

    
Vitamins (e.g. Vitamin A, Vitamins B, and    Vitamin C)
    

      
Cellular proliferation;
      
Collagen synthesis stimulation;
      
Immune system stimulation.
    
  
  

    
Zn
    

      
Cell growth;
      
Protein synthesis;
      
Anti-inflammatory activity;
      
Anti-microbial activity.
    
  

Table 1: Nutrients and the possible role of their supplementation in the management of chronic wound.

Arginine

Arginine has many functions in human organism that could be correlated with wound healing processes [18]. It is involved in protein synthesis and induce the release of growth hormone, prolactin, and insulin. Is therefore indirectly involved in polyamines synthesis, responsible for cell division, differentiation, and growth [18]. Arginine is a precursor of proline and hydroxyproline, which are important for the synthesis of collagen. Arginine represents the substrate of Nitric Oxide synthase (iNOs), which converts arginine to Nitric Oxide (NO). Nitric oxide, a known immune response mediator, also plays a central role in skin repair improving the vasodilatation and stimulating the secretion of growth hormones and insulin-like growth factor [18]. The human body is able to synthetize arginine, however in presence of a stressful state and insufficient nutritional intake, arginine supplementation could be suggested for adequate muscle and connective tissue growth. The effect of oral arginine supplementation in pressure ulcers has been evaluated. Different in vivo human trials (including open trials and randomised clinical trials) were conducted, enrolling in total 645 patients with PUs (stages II, III or IV) [19]. In these trials the protein-enriched oral nutritional supplementation was consumed one to three times/day and contained 3–9g of arginine/dose, until a maximum of 18g arginine/day. The majority of the considered studies supported the positive effect of nutritional supplementation with additional protein, arginine and micronutrients on PU healing. To confirm the role of arginine Cereda et al. observed that a nutritional formula enriched with proteins, arginine, zinc, and vitamin C was able to accelerate the rate of PU healing, compared to a standardized formula with a similar protein content [20]. Leigh et al. evaluated the effect on PUs healing of two different daily doses of arginine (4.5g and 9g) in 23 hospital patients. Both doses significant decreased the PUs severity (reduction in PU area and Pressure Ulcer Score for Healing) without differences between the two dosages considered. Therefore, the authors concluded that a lower dosage of arginine could be sufficient to increase the PU healing [21]. On the other hand, in a meta-analysis conducted by Cheshmeh et al. was reported that higher doses of arginine supplement had a greater effect on reducing the probability of PU development [22]. In conclusion, there are some evidences of improved healing with an arginine enriched mixed nutritional supplements containing other micronutrients (such as vitamin C and Zn) compared with standard diet. Although other studies are necessary to confirm the role of arginine supplementation alone, it seems to represent an important key nutrient in pressure ulcer healing.

Glutamine

Glutamine is a conditionally essential amino acid [23]; it can be synthetized by human body however during stress conditions its level may be depleted. Glutamine represents a fuel source for cells with rapid turnover (e.g. enterocytes, epithelial cells, fibroblasts, macrophages, and lymphocytes) and plays a key role for the immune system [24]. Glutamine is known to play a regulatory role in different cellular processes including: metabolism, cell integrity, protein synthesis and extracellular matrix synthesis. Indeed, glutamine is able to stimulate the synthesis of collagen representing a precursor of proline and hydrooxyproline residues [25]. Two studies observed a faster wound healing rates in severe burns after enteral glutamine supplementation [26,27]. Although no specific studies have been conducted on wound healing for pressure ulcer patients and glutamine supplementation alone, some amino acids mixture (containing β-hydroxy β-methylbutyrate, arginine and glutamine), may improve tissue viability and overall wound conditions in patients with PU [23,28].

Hydroxy-Methylbutyrate

Hydroxy-Methylbutyrate (HMB) is a metabolite of leucine, an essential amino acid. HMB, inhibiting proteolysis and modulating protein turnover, it is associated with muscle mass increment and collagen synthesis. Therefore, it could stimulate the wound-healing processes [23]. The supplementation of amino acids mixture (containing HMB, arginine and glutamine) has been reported to improve wound healing processes [23,29]. In these studies, is difficult to identify the direct effect of the active ingredients. However, in a study conducted by Chang et al., a diet with HMB was compared with other available enteral nutrition. A significant reduction in mortality and pressure ulcers were observe in HMB group compared to the control group [30].

Vitamins

Some micronutrients, such as vitamins B and C, become deficient at old age [31] and their supplementations could have an interesting role in pressure ulcer healing. Vitamin A plays stimulatory activity on immune system, contributes to maintain epithelial integrity, and stimulate collagen synthesis. Vitamin C exerts a role in fibroblast maturation and collagen formation. Both vitamins A and C could have a role in wound healing process [32].

Vitamins B are water soluble vitamins involve in different process, they promote cells proliferation and muscle tone, improve metabolic rate, and stimulate immune and nervous systems. Vitamins B deficiency, in particular Vitamin B1 (thiamine) deficiency, could be involved in many disorders characterized by skin manifestation and could weaken wound healing process [33].

Zinc

Zn is an essential element; it is an important cofactor of numerous enzymatic reactions involved in cell growth and protein synthesis [34]; therefore, it could play an important role in wound healing process. Zn also exerts anti-inflammatory and anti-microbial effects [31]. Zinc is usually supplemented to promote heeling, although their efficacy has not to be conclusive demonstrated [4,10]. Delayed in wound healing have been associated to zinc deficiency. Although there are no evidences that supported the positive effect of Zn on wound healing in absence of deficiencies, the assessment of Zn state is not easy, therefore the routine supplementation of this micronutrients for PU patients at high risk for zinc deficiency is usual in clinical practice.

Conclusions

Pressure ulcers are an important healthcare issue, that affect the quality of life of patients and is associated with a significant economic burden. Different factors could contribute to the development of PUs, among which malnutrition and sarcopenia. Although there is no clear evidence that nutritional intervention reduce the development of PU, due to the limitations associated to the in vivo studies, difference guidelines, include the guideline by the European Pressure Ulcer Advisory Panel, National Pressure Injury Advisory Panel, and Pan Pacific Pressure Injury Alliance, recommends use of a high-protein, high-calorie oral nutrition supplement fortified also with arginine and other antioxidants to treat adults with grade 2 or greater pressure injury and who are malnourished or at risk of malnutrition [14]. Recent ESPEN guidelines suggested that in patients with bedsore specific amino acids such as arginine, glutamine, and β hydroxy β methylbutyrate can be added to oral/enteral foods to improve and accelerate the wound healing process [35]. These amino acids have also shown positive effects in the framework of sarcopenia [36]. Different products suitable for this kind of patients are available on the market; a food for special medical purposes containing essential amino acids, arginine, glutamine, HMB, vitamins B, and Zn has been recently commercialized*. Its components could counteract different factors involved in the pathogenesis of PUs or chronic wounds (Figure 1).

    

    

    Figure 1: Factors involved in the pathogenesis of Pressure Ulcers (PU) and possible mechanisms of action of nutritional components contain in foods for medical purposes commercial available.