Utilizing Citrulline as an Efficient Arginine Supplement for Wound Healing

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Nutritional recommendations for wound healing are based on the patient receiving an adequate number of calories each day consisting of the proper mix of macronutrients, namely proteins, fats, and carbohydrates. Each of the macronutrients is important, but in wound healing, a special focus is placed on protein because protein is the only macronutrient that contains nitrogen. Protein is composed of a variety of amino acids. Arginine is one of these amino acids, but to understand where citrulline fits into the wound-healing puzzle, you must first understand the role of amino acids in general and, specifically, the role of arginine.

The Role of Amino Acids

It often is said that amino acids are the building blocks of protein. This is a way to describe that protein foods, such as beef, chicken, and fish, consist of various-length chains of amino acids, which are broken down by digestion. Simply put, once a protein source (eg, a chicken breast) reaches the stomach, hydrochloric acid and enzymes called proteases break the protein down into smaller chains of amino acids and then into individual amino acids.

All amino acids have the same basic structure: a central carbon, at least one amino group (NH2), at least one carboxylic acid group (-COOH), and a side chain group that makes each amino acid unique and determines its functional role in the body.¹ Although sometimes classified by their properties, such as net charge and polarity, the 20 common amino acids often are grouped into two categories termed dispensable or indispensable amino acids. Earlier terminology was nonessential or essential amino acids, respectively, and sometimes these older terms still are used.

The human body cannot synthesize the 9 indispensable amino acids; therefore, individuals must consume them in their diet.¹ The remaining amino acids are considered dispensable because the body can synthesize them using existing carbon skeletons and free amino groups.² However, some nonessential amino acids are considered conditionally indispensable. Conditionally indispensable is defined as requiring a dietary source when endogenous synthesis cannot meet metabolic needs. This may occur for a specific reason, such as genetic conditions like phenylketonuria or immature organ function during infancy and childhood, which prevents the body from synthesizing the amino acid.¹ For others, the demand increases during times of metabolic stress, such as in the presence of a chronic wound. It then becomes questionable if the body’s production can keep up with the increased demands.

Arginine is in this conditionally indispensable category because arginine requirements increase during wound healing.³ The common amino acids are indispensable, dispensable, and conditionally indispensable.⁴

Arginine in Wound Healing

Arginine has many functions in the body, but in wound healing, its function as a precursor to nitric oxide (NO) is of particular interest. NO is essential to wound healing. NO is produced from arginine and oxygen in a reaction catalyzed by the enzyme nitric oxide synthase. NO acts as a host-protective agent by killing pathogens and increasing blood flow to wounds.⁵ By relaxing the inner lining of muscles in blood vessels, NO causes the vessels to dilate and increase circulation. Therefore, NO can indirectly aid a wound site by delivering sufficient nutrients and adequate oxygen.

Arginine also serves as an intermediate amino acid during proline synthesis, which is required for wound healing and collagen synthesis.⁶ Arginine has several additional functions that support wound healing, so supplementation has become somewhat routine. A variety of medical nutritional products include arginine as an ingredient.

Citrulline in Wound Healing

Citrulline is also a nonessential amino acid, meaning the body can synthesize it endogenously. Diet is a poor source of citrulline because it is primarily found in watermelon juice and rind.⁷ The function of citrulline is to produce arginine, which is why it is linked to wound healing. It is well accepted that arginine is essential for wound healing and NO production, so the obvious next step is for researchers to find the most optimal way to ensure an adequate amount of arginine is onboard.

A simple way to think of it is that citrulline is a precursor to arginine. The only function of citrulline is its conversion to arginine. A study comparing the relative efficiency of arginine and citrulline supplementation conducted in mice concluded that citrulline supplementation may increase arginine availability even more than arginine supplementation itself.⁸

Outside of wound healing, healthy people take citrulline supplements for various reasons, including improved athletic performance, lowering blood pressure, and alleviating erectile dysfunction.9

Arginine Versus Citrulline in Wound Healing

Arginine supplementation has some drawbacks. The primary challenge is the loss of arginine during the first-pass metabolism. The first-pass effect, also known as presystemic metabolism, refers to the metabolism of drugs or chemicals in the liver or intestine before they reach the systemic circulation.¹⁰ Approximately 40% of dietary arginine is lost during this first-pass effect,¹¹ while citrulline undergoes limited degradation. Arginine is largely metabolized by the liver, whereas the liver does not take up citrulline; therefore, nearly all the citrulline absorbed from the small intestine bypasses the liver and enters the systemic circulation.¹²

Other reported challenges with chronic arginine supplementation include gastrointestinal problems and diarrhea.¹³ This effect is dose-dependent, with studies varying from 3 g/day to more than 100 g/day. Although the daily dose provided by typical wound supplements probably will not provoke any stomach issues, patients often complain that they believe the nutritional supplement affected them. If a patient believes this is true and stops consuming the supplement, the practitioner is back to square one and must find another intervention.

Finally, the controversy regarding the use of arginine in hemodynamically unstable patients and critically ill patients persists. While this controversy should no longer exist,¹⁴ it is still brought up at every major wound meeting, indicating that it is still an unanswered question in practitioners’ minds. The conversion of citrulline to arginine occurs continuously, as long as citrulline is circulating in the bloodstream.¹⁵ This will maintain a steady release of NO, which may address this issue.

Putting Research Into Practice

Medicine evolves as researchers uncover new information and industry translates this research into medical products. Medical nutrition therapy is no different; arginine and citrulline represent this evolution. Ten years ago, arginine was viewed skeptically, but eventually, sufficient research put it into the mainstream. Now citrulline has come on the scene and may become an improvement over arginine. As with all nutrition interventions, the key is palatability and consumption by the patient. If the patient does not consume it, it does not matter what ingredients are in the product.

In Conclusion

New products containing citrulline are currently available. These products offer another option in medical nutrition therapy. The nutrition care process requires not only assessment and intervention but also monitoring and evaluating the care plan. If one product is not working or not consumed by the patient, clinicians should try something different. Citrulline-enriched products offer an alternate way to provide arginine and another viable option in getting the patient healed, which is the main goal.

Dr. Nancy Collins is a wound care–certified registered dietitian nutritionist based in Las Vegas, NV. She is well known for her expertise in the complex relationship among malnutrition, body composition, and tissue regeneration. To contact Dr. Collins, visit her website at www.drnancycollins.com.

This article originally appeared here in Wound Management and Prevention. It has been adapted with permission.

References
1. Gropper S, Smith J. Advanced Nutrition and Human Metabolism. 6th ed. Cengage Learning; 2013.
2. Mahan LK, Escott-Stump S, Raymond J. Krause’s Food & the Nutrition Care Process. 13th ed, vol 1. WB Saunders Co; 2012.
3. Nelms M, Sucher KP, Lacey K, Roth SL. Nutrition Therapy & Pathophysiology. 2nd ed. Brooks/Cole Cengage Learning; 2011.
4. Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. The National Academies Press; 2002:593.
5. Stechmiller JK, Childress B, Cowan L. Arginine supplementation and wound healing. Nutr Clin Pract. 2005;20(1):52-61. doi:10.1177/011542650502000152
6. Alexander JW, Supp DM. Role of arginine and omega-3 fatty acids in wound healing and infection. Adv Wound Care. 2014;3(11):682-690. doi:10.1089/wound.2013.0469
7. Rimando AM, Perkins-Veazie PM. Determination of citrulline in watermelon rind. J Chromatogr A. 2005;1078(1-2):196-200. doi:10.1016/j.chroma.2005.05.009
8. Agarwal U, Didelija IC, Yuan Y, Wang X, Marini JC. Supplemental citrulline is more efficient than arginine in increasing systemic arginine availability in mice. J Nutr. 2017;147(4):596-602. doi:10.3945/jn.116.240382
9. L-citrulline. Rx list. Accessed September 27, 2022.
10. Kenyon EM, Hughes MF. Oral exposure and absorption of toxicants. Comprehensive Toxicology. 2nd ed, vol 1. Elsevier: 2010:61-74.
11. Wu G. Intestinal mucosal amino acid catabolism. J Nutr. 1998;128(8):1249-1252. doi:10.1093/jn/128.8.1249
12. Morris SM Jr. Regulation of enzymes of the urea cycle and arginine metabolism. Annu Rev Nutr. 2002;22:87-105. doi:10.1146/annurev.nutr.22.110801.140547
13. Grimble GK. Adverse gastrointestinal effects of arginine and related amino acids. J Nutr. 2007;137(6 suppl 2):1693S-1701S. doi:10.1093/jn/137.6.1693S
14. Rosenthal MD, Rosenthal C, Patel J, Jordan J, Go K, Moore FA. Arginine in the critically ill: can we finally push past the controversy? Int J Crit Care Emerg Med. 2016;2(2). doi:10.23937/2474-3674/1510017
15. Lee SK. Citrulline: an innovative pharmaconutrient that accelerates the healing of wounds. CiteSeerX. Accessed September 27, 2022.