Homocysteine - A Stealth Mediator of Impaired Wound Healing: A Preliminary Study

Joseph V. Boykin, Jr., MD; Chris Baylis, PhD


Wounds. 2006;18(4):101-116. 

In This Article

Abstract and Introduction


The objective of this study was to clinically evaluate the amino acid homocysteine (Hcy) as a risk factor for impaired wound healing in 12 patients receiving topical human fibroblast-derived dermal substitute treatment for nonhealing lower-extremity wounds. Homocysteine is a significant risk factor for atherosclerotic vascular disease and is an inhibitor of nitric oxide (NO) bioactivity. The data from this preliminary study documented a correlation between elevated serum Hcy, significantly (P < 0.05) decreased wound NO bioactivity by measurement of wound fluid nitrate and nitrite (NOx, the stable oxidation products of NO), and impaired wound healing. In a single case report, successful treatment of elevated Hcy was documented to restore normal wound healing. In the authors' wound center, untreated, elevated Hcy was observed in 50% of patients with chronic, nonhealing wounds, 63% of patients with diabetic, neuropathic ulcers, and 47% of patients without diabetes with chronic, venous stasis ulcerations (n = 138). Elevated Hcy may inhibit wound NO bioactivity and impair wound healing by multiple pathways and may also alter wound granulation tissue formation by occupying the fibronectin domain of fibrin during provisional wound matrix formation. The authors suggest 1) that elevated Hcy may be a frequently encountered risk factor for impaired wound healing that may promote chronic wound development by significantly decreasing wound NO bioactivity and, perhaps, by modification of provisional wound matrix formation and 2) that the preferred treatment of elevated Hcy is with daily administration of L-methylfolate, pyridoxal 5'-phosphate, and methylcobalamin.


Nitric oxide (NO), a gaseous free radical, is a critical mediator of normal tissue repair.[1] Angiogenesis,[2] granulation tissue formation,[3] epidermal migration,[4] and collagen deposition [5] are all significant wound repair processes that are regulated by NO bioactivity. General somatic and wound NO bioactivity may be evaluated by measuring nitrate and nitrite (NOx, the stable oxidation products of NO) from plasma and urine and from wound fluid NOx, respectively. In experimental and clinical wound healing research, NOx has been used extensively as a reliable surrogate marker for NO.[1,3,5,6,7,8] In all cases, NOx determinations have been highly sensitive to conditions or factors that reduce NO production and impair normal wound healing, such as diabetes,[9] protein-calorie malnutrition,[10] cutaneous irradiation,[11] steroid therapy,[12] and metabolic inhibition of NO synthesis.[13] In these cases, decreased wound fluid NOx and impaired wound closure were associated with decreased collagen accumulation,[14] wound tensile strength, type I and III collagen gene expression,[15] vascular endothelial growth factor (VEGF) expression, granulation tissue formation, and wound microvascular perfusion.[16]

Elevated homocysteine (Hcy) is widely accepted as a novel risk factor associated with atherosclerotic cardiovascular disease (CVD) in the coronary, cerebral, and peripheral vascular beds.[17] Homocysteine also is believed to antagonize NO bioactivity by multiple pathways but has not been identified as a risk factor for wound repair. This preliminary study was designed to prospectively document the relationship between impaired wound healing, wound NO bioactivity evaluated by wound fluid NOx measurement, and elevated Hcy while using topical human fibroblast-derived dermal substitute (Dermagraft® Human Fibroblast-Derived Dermal Substitute, Smith & Nephew Inc., Largo, Fla) for the treatment of chronic lower-extremity ulcers.