Leg Ulcers: Biochemical Factors

Abstract

Objective:

To review the biochemical mechanisms underlying the development of skin changes leading to ulceration in patients with chronic venous disease.

Methods:

Searches of Medline and Embase medical literature databases were undertaken. Cochrane Reviews were studied for relevant articles. Hand-searching of non-indexed journals was undertaken.

Synthesis:

Increased leucocyte activation has been shown in patients with venous disease as well as increased expression of soluble endothelial adhesion molecules. Histological studies of the skin in patients with chronic venous disease show a pervascular infiltration of the capillaries of the papillary plexus (the most superficial part of the dermis) with monocytes, macrophages and connective tissue proteins including fibrin. Fibrosis of the skin and subcutaneous tissues may be initiated by increased gene expression and production of transforming growth factor-beta₁. Vascular endothelial growth factor may be involved in the capillary proliferation that has been reported in the skin by a number of authors. Increased expression of several tissue metalloproteinases (MMPs) has been reported both in lipsclerotic skin and peri-ulcer skin. The tissue inhibitors of metalloproteinases (TIMPs) are also increased and the net result is unclear. Treatment of venous disease using micronised purified flavonoid fraction moderates some of the inflammatory markers, including leucocyte ligand expression and endothelial adhesion molecule shedding. These compounds have also been shown to reduce leucocyte-endothelial adhesion in animal models of ischaemia-reperfusion injury.

Conclusions:

Many inflammatory processes have now been shown to be involved in the development of the skin changes in patients with chronic venous disease. However, the precise sequence of events which leads to leg ulceration is still unclear. Pharmacological treatments aimed at moderating some of these inflammatory processes are now under investigation as potential ways of treating patients with the more advanced stages of venous disease.