Liposclerotic Skin Research Articles

Indikation und Methode der LAF-Therapie

A variety of techniques for leg ulcer surgery have been developed in the last 20 years. In literature these techniques are always presented as competitive surgical methods for treating different forms of leg ulcers and are compared regarding their success. From our point of view, this approach seems inappropriate. Essentially there are 3 different techniques available: shave therapy, LAF therapy (removal of liposclerosis and fasciotomy) and fasciectomy. The choice of methods must be based on a classification of the ulcers, as each procedure is not suitable for ever type of ulcer. First we have to differentiate between venous ulcers and mixed leg ulcers. The venous ulcers should then be subdivided in ulcers developed in liposclerotic skin and ulcers which developed in atrophie blanche lesions. Finally the liposclerotic ulcers are classified according to Hach's classification system into 4 stages. In case of mixed leg ulcers with relevant occlusive arterial disease, attention should first be directed to improving the arterial blood supply; further approaches depend on how successful this is.

Vasodilatory capacity of the skin in venous disease and its relationship to transcutaneous oxygen tension

Low transcutaneous oxygen tension (Ptc,O2) values in the supramalleolar skin of patients with venous disease are often reported. This measurement involves heating the skin to 43 degrees C to cause maximum vasodilatation and is valid only if liposclerotic and normal skin can vasodilate to the same degree. Forty-four limbs were studied, 15 with lipodermatosclerosis (LDS), 14 with uncomplicated varicose veins, and 15 controls. A Ptc,O2 electrode was modified to incorporate a laser Doppler probe. Laser Doppler flux was measured in the supramalleolar skin before and after local heating to 43 degrees C and the relative increase in flux was measured. The Ptc,O2 was then measured at the same site and on the chest. Vasodilatory capacity was expressed as the ratio of peak:basal laser Doppler flow, and the Ptc,O2 was expressed as a leg:chest ratio. Median laser Doppler flow was higher in limbs with LDS (median 67 mV) than in normal limbs (median 40 mV) (P less than 0.03). Ptc,O2 was higher in control limbs (median ratio 0.94) than in limbs with LDS (median 0.53) (P less than 0.006). The microcirculation in LDS had less capacity to vasodilate after heating (median factor of increase 5.4) than normal skin (median factor of increase 12.3) (P less than 0.001). A simple regression analysis was performed on all pairs of data, and revealed a correlation between Ptc,O2 and vasodilatory capacity (r = 0.524, P less than 0.001). The results indicate that low Ptc,O2 levels in venous disease reflect an inability of the microcirculation to increase its flow in response to local heating; inferences about the oxygen content of liposclerotic skin at normal temperatures cannot be drawn using this technique.

Update on chronic-venous-insufficiency-induced inflammatory processes.

The causes of venous ulceration remain unclear. Twentieth-century hypotheses concentrated on the possibility that this problem was caused by failure of oxygen delivery to the skin. However, it has been difficult to substantiate these predictions in practice. Although the presence of tissue hypoxia has been suggested by studies in which transcutaneous oxygen tension has been assessed with transducers heated to unphysiological temperatures, when oxygen measurements are made at room temperature there is little evidence of tissue hypoxia. This has led to the assessment of alternative mechanisms of ulcer development. There has been considerable interest in recent years in the inflammatory processes that surround venous ulceration. A complex sequence of events appears to surround the development of leg ulceration. Increased leukocyte activation has been shown in patients with venous disease as well as increased expression of soluble endothelial adhesion molecules. Histologic studies of the skin in patients with chronic venous disease show a perivascular 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 has been reported both in liposclerotic skin and periulcer skin. The tissue inhibitors of metalloproteinases are also increased and the net result is unclear. Treatment of venous disease using micronized purified flavonoid fraction moderates some of the inflammatory markers, including leukocyte ligand expression and endothelial adhesion molecule shedding. These compounds have also been shown to reduce leukocyte-endothelial adhesion in animal models of ischemia-reperfusion injury. 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 that leads to leg ulceration is still unclear. Pharmacologic 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.

Lipodermatosclerosis and the significance of proteolytic remodeling in the pathogenesis of venous ulceration (Review).

The preceding stage of venous ulceration represents a scleroderma-like hardening of the skin called lipodermatosclerosis. Clinical stages such as lipodermatosclerosis and venous ulceration, which succeed one another are highly associated to chronic venous insufficiency. Lipodermatosclerosis is characterized by fibrous scar tissue of the reticular dermis built up of collagen bundles and loss of cellular components, whereas venous ulceration is characterized by total loss of epidermis and partially of matrix structures in the upper dermis. There is a growing recognition that an excessive proteolytic activity by proteases, in particular that of matrix metalloproteinases and fibrinolytic factors of the plasminogen activation system may be a key feature in the pathophysiological understanding of venous leg ulcer formation. Lipodermatosclerosis displays an intense ongoing proteolytic process by elevated matrix metalloproteinase activity, as recently shown on different molecular and biological levels. Elevated expression on mRNA and protein level of matrix metalloproteinases and fibrinolytic factors of the plasminogen activation system have been detected in liposclerotic skin lesions. In addition, matrix metalloproteinases were proteolytically activated confirmed by zymography experiments and collagen degradation assays. Therefore it is well conceivable, that proteolytic enzymes of matrix metalloproteinases could initiate an elevated turnover of the extracellular matrix with subsequent breakdown of the matrix scaffold finally resulting in venous ulceration.

Presidential address: Venous disorders—Reflections of the past three decades

Presidential address: Venous disorders—Reflections of the past three decades

Free tissue transfer in treatment of the recalcitrant chronic venous ulcer.

We propose that a long-term cure for the recalcitrant chronic venous ulcer must involve a dual surgical approach including (1) wide excision of the ulcer and surrounding liposclerotic tissue bed, and (2) replacement by a free flap containing multiple, competent microvenous valves with a normal microcirculation. Advantages of free flaps over skin grafting include improvement of the underlying pathophysiology; increase in blood supply to the area; ability to cover exposed bone, joint, or tendon; and a lower incidence of recurrence. During the past 8 years, 20 consecutive muscle free flaps were performed in 18 patients for 19 recalcitrant venous ulcers (two "sequential" flaps to the ipsilateral leg in 1 patient and a repeat flap after initial failure in 1 patient). Twelve males and 6 females ranged in age from 17 to 76 years (mean, 44 years). Nontraumatic, nonosteomyelitic venous ulcers had been present for an average of 3.5 years (range, 1-10 years) and failed an average of 2.4 skin grafts (range, 0-6 grafts). Defects ranged from 100 to 600 cm2 (mean, 238 cm2). Donor tissues included rectus abdominis (N = 13), latissimus dorsi (N = 5), gracilis (N = 1), and serratus (N = 1) muscles. Recipient vessels included posterior tibial (N = 12), anterior tibial (N = 6), and peroneal (N = 2). In all instances except one, only one vein, usually one of the venae comitantes, was anastomosed in end-to-end fashion. Successful free tissue transfer was accomplished in 18 of 20 flaps (90%). Complications included infection with partial flap and/or skin graft loss (three flaps), and partial skin graft loss (two flaps). There were no recurrences within the flaps; however, breakdown occurred at the junction between the flap and residual adjacent liposclerotic skin in 1 patient. Follow-up average 32.7 months (range, 8-65 months); 3 patients were lost to follow-up. Free muscle transfer can provide a long-term cure for the recalcitrant venous ulcer by replacing the diseased tissue bed with healthy tissue containing multiple, competent microvenous valves and a normal microcirculation. This can be accomplished in one reconstructive procedure with excellent long-term results.

Effect of Compression Stockings on the Skin Microcirculation in Chronic Venous Insufficiency

Objective: To use a single fibre laser Doppler fluxmeter to assess the microcirculatory effects of compression stockings. Design: Controlled study comprising patient and control groups. Setting: Department of Surgery, University College London Medical School, London, UK. Patients and participants: Ten patients with lipodermatosclerosis caused by chronic venous insufficiency and 10 control subjects. Interventions: Measurements were made from the liposclerotic skin of patients and 8 cm above the medial malleolus in controls. Laser Doppler flux (LDF), blood ce velocity (BCV) and concentration of moving blood cells (CMBC) were recorded with the subject lying supine. A class II graduated compression stocking was applied to the leg and laser Doppler recordings were repeated. The protocol was repeated with the subject sitting. Main outcome measures: The effects of a compression stocking on LDF, BCV and CMBC in the horizontal and sitting positions were measured. Results: In patients in the supine position, the compression stocking resulted in a 28% median increase in LDF ( p = 0.03), with a corresponding 29% median increase in BCV. There was no significant change in CMBC. In the sitting position, the compression stocking caused a 105% median increase in LDF ( p < 0.01) due to a corresponding 89% median increase in BCV ( p = 0.01); there was only 25% median increase in CMBC. The effects of compression in controls were similar to those in patients. Conclusion: Compression stockings may be effective in the treatment of chronic venous insufficiency by increasing the microcirculatory flow velocity.

Effect of leg elevation on the skin microcirculation in chronic venous insufficiency

Leg elevation is advised in the treatment of venous disease associated with edema. We have used laser Doppler fluxmetry to assess the effects of leg elevation on the skin microcirculation. Fifteen patients with lipodermatosclerosis caused by chronic venous insufficiency and 15 control subjects were studied. Measurements were made from the liposclerotic skin of patients and 8 cm above the medial malleolus in control subjects. Laser Doppler flux, blood cell velocity, and concentration of moving blood cells were recorded with the subject lying in the supine position and after elevating the foot 30 cm above the heart level. In subjects in the horizontal position, the resting laser Doppler flux was significantly higher in patients with lipodermatosclerosis than in control subjects (median difference 63 arbitrary units; 95% confidence interval: 36, 108). This difference was due to a higher concentration of moving blood cells in the patient group (median difference 6.5 arbitrary units; 95% confidence interval: 3.4, 9). The blood cell velocity was not statistically significant between the two groups. On leg elevation, there was a substantial increase in the laser Doppler flux in the patient group; the median percentage increase in flux was 45% (p < 0.01). This was due to an increase in blood cell velocity; the median percentage increase was 41% (p < 0.01). There was no corresponding change in the concentration of moving blood cells. The results in the control group showed a similar trend but have not reached statistical significance. We conclude that limb elevation enhanced the microcirculatory flow velocity in liposclerotic skin of patients with chronic venous insufficiency.

Skin Blood Flow in Chronic Venous Insufficiency

Objective: To evaluate the skin temperature, laser Doppler flux (LDF), concentration of moving blood cells (CMBC) and speed of blood cells (SBC) in the liposclerotic and clinically normal skin of patients with chronic venous insufficiency. Design: Parallel groups study comparing patients with chronic venous insufficiency with control subjects. Setting: Vascular laboratory, Middlesex Hospital, University College and Middlesex School of Medicine, London, UK. Participants: Twenty patients with lipodermatosclerosis and chronic venous insufficiency comprised the disease group, and 15 subjects without venous disease comprised the control group. Main outcome measures: The skin temperature, LDF, CMBC and SBC were assessed in the gaiter area and on the dorsum of the foot. Results: A higher LDF (median LDF and interquartile range (IQR) = 132 (66–289), p = 0.001 (Mann-Whitney) and skin temperature (Median temperature and IQR = 31.1 (29.6–32.4), p = 0.001) was found in the liposclerotic skin of patients with chronic venous insufficiency compared with normal controls (median LDF and IQR = 49 (32–58); median temperature and IQR = 28 (27–30.3)). Similarly the LDF on the dorsum of the foot (median LDF and IQR = 73 (59–127), p = 0.03) and skin temperature on the dorsum of the foot (median temperature and IQR = 31.1 (30.4–32.1), p = 0.002) was significantly higher in the patients with chronic venous insufficiency compared with normal controls (median LDF and IQR = 55 (36–66), median temperature and IQR = 29.5 (26.7–30.7)). Conclusions: This study demonstrates that there is increased skin blood flow in both liposclerotic skin and clinically normal skin in patients with chronic venous insufficiency.

Leukocytes: Their role in the etiopathogenesis of skin damage in venous disease

The role of leukocytes in tissue damage in the liposclerotic skin of venous disease has been investigated. Twenty-eight skin biopsy specimens were obtained from 23 patients with varicose veins of the lower limb, with a spectrum of skin injury ranging from normal to severe liposclerosis. In no patient was a venous ulcer present. Immunohistochemistry was used to determine the cell types present and provide an indication of their activity. The predominant infiltrating cell types present were T lymphocytes and macrophages. B cells and neutrophils were rarely seen. As described previously, the capillaries were greatly increased in number in the papillary dermis and exhibited grossly increased expression of factor VIII-related antigen and major histocompatibility complex class II. Surprisingly, expression of adhesion molecules endothelial leukocyte adhesion molecule-I and vascular cell adhesion molecule were not elevated, but intercellular adhesion molecule-I expression did increase in more severely diseased skin. Perivascular fibrin was seen occasionally, but there was no evidence of microvascular occlusion. Staining for the cytokine tumor necrosis factor-α was not increased in liposclerotic skin. Dermal staining for both interleukin (IL)-1α and IL-1β was increased in severely liposclerotic skin, but this was not seen at an early stage. Epidermal staining for IL-1α and IL-1β was not increased. All changes were confined to the subpapillary region of the skin. These findings demonstrate that accumulation of macrophages and T cells is an event associated with the development of liposclerotic skin changes that may lead to ulceration in venous disease. However, no evidence was found to suggest that hypoxia caused by occlusion of vessels by leukocytes or other mechanisms of microvascular insufficiency contribute. No evidence was found to implicate either tumor necrosis factor-α or epidermal IL-1 in the initiation of leukocyte infiltration, but an increase in dermal IL-1 may be involved in later stages of the process.

Peripheral nerve function in chronic venous insufficiency

Abnormalities of vasomotion, impairment of the venoarteriolar reflex and increased skin blood flow reported in the liposclerotic skin of patients with chronic venous insufficiency (CVI) suggest altered nervous control of the skin microcirculation. The aim of this study was to determine whether patients with CVI have a peripheral neuropathy. Forty patients with CVI and lipodermatosclerosis (LDS) and 35 age and sex-matched controls were examined for neuropathy using three modalities of testing. Threshold to warming was used to assess unmyelinated fibres, and threshold to cooling and vibration to assess myelinated fibres. Warming and cooling thresholds were measured on the sole of the foot by a purpose built, computer controlled instrument. The threshold to vibration was measured on the big toe using the Ohio Bio-thesiometer. A significantly raised threshold to warming and vibration was found in the CVI group compared to the normal controls [median threshold to warming (interquartile range) in CVI group = 5.3 (0.1-9.1) median threshold to warming (interquartile range) in controls = 1.21 (0.17-3.5), p = 0.005 and median threshold to vibration (interquartile range) in CVI group = 22 (13-31) median threshold to vibration (interquartile range) in controls = 12 (8.5-27.5), p = 0.024]. The thresholds to cooling was not statistically different in the two groups. This study demonstrates the presence of a peripheral neuropathy in patients with chronic venous insufficiency, and this may be important in the pathogenesis of venous ulceration.

Three Tests of Microcirculatory Function in the Evaluation of Treatment for Chronic Venous Insufficiency

No investigation exists which has been shown to detect accurately microcirculatory improvement following treatment for chronic venous insufficiency. This study examines three possible techniques for doing so.Fourteen patients with chronic venous insufficiency and fourteen controls underwent measurement of transcutaneous PO2,133xenon clearance from the skin and subcutaneous tissues and laser–Doppler flowmetry in the gaiter region. Patients with venous disease then followed a regime of intermittent pneumatic compression for 4 h each day for 4 weeks. The same measurements were then repeated. Xenon clearance from subcutaneous fat and the time taken to reach maximal laser–Doppler flow after release of a tourniquet showed a significant improvement after compression treatment. These tests may be useful as parameters in the objective monitoring of response to treatment in patients with liposclerotic skin.