Chronic venous disease of the lower limbs is manifested by a range of signs, the most obvious of which are varicose veins and venous ulcers. However, the signs also include edema, venous eczema, hyperpigmentation of skin of the ankle, atrophie blanche (white scar tissue), and lipodermatosclerosis
(induration caused by fibrosis of the subcutaneous fat).
Chronic venous disease can be graded according to the descriptive clinical, etiologic, anatomical, and pathophysiological (CEAP) classification, which provides an orderly framework for communication and decision making.1,2 The clinical signs in the affected legs are categorized into seven classes designated C0 to C6.
Prevalence
Chronic venous disease is extremely common, although the prevalence estimates vary. A cross-sectional study of a random sample of 1566 subjects 18 to 64 years of age from the general population in Edinburgh, Scotland,3 found that telangiectases and reticular veins were each present in approximately 80 percent of men and 85 percent of women. Varicose veins were present in 40 percent of men and 16 percent of women, whereas ankle edema was present in 7 percent of men and 16 percent of women.3 Active or healed venous leg ulcers occur in approximately 1 percent of the general population.3,4Although not restricted to the elderly, the prevalence of chronic venous disease, especially leg ulcers, increases with age.3-5 Most studies have shown that chronic venous disease is more prevalent among women, although in a recent study, the difference between sexes was small.6 In the Framingham Study, the annual incidence of varicose veins was 2.6 percent among women and 1.9 percent among men,7 and in contrast to the Edinburgh Vein Study, the prevalence of varicose veins was higher in men.3,8 In the San Diego Population Study, chronic venous disease was more prevalent in populations of European origin than in blacks or Asians.9 Risk factors for chronic venous disease include heredity, age, female sex, obesity especially in women), pregnancy, prolonged standing, and greater height.
Economic impact
In a population study in the United Kingdom, the median duration of ulceration was nine months, 20 percent of ulcers had not healed within two years, and 66 percent of patients had episodes of ulceration lasting longer than five years.
Symptoms
Symptoms traditionally ascribed to chronic venous disease include aching, heaviness, a feeling of swelling, cramps, itching, tingling, and restless legs. Chronic venous disease is associated with a reduced quality of life, particularly in relation to pain, physical function, and mobility. It is also associated with depression and social isolation.19 Venous leg ulcers, the most severe manifestationof chronic venous disease, are usually painful20 and affect the quality of life.
VENOUS HYPERTENSION
Despite the diversity of signs and symptoms associated with chronic venous disease, it seems likely that all are related to venous hypertension. In most cases, venous hypertension is caused by reflux through incompetent valves,6,24 but other causes include venous outflow obstruction and failure of the calf-muscle pump owing to obesity or leg immobility. Reflux may occur in the superficial or deep venous system or in both. A review of 1153 cases of ulcerated legs with reflux found superficial reflux alone in 45 percent, deep reflux alone in 12 percent, and both forms in 43 percent. 25 An analysis of cases of chronic venous disease indicated that primary valvular incompetence was present in 70 to 80 percent and a congenital anomaly in 1 to 3 percent; valvular incompetence was due to trauma or deep-vein thrombosis in 18 to 25 percent.
Pressure in the veins of the leg is determined by two components: a hydrostatic component related to the weight of the column of blood from the right atrium to the foot and a hydrodynamic component related to pressures generated by contractions of the skeletal muscles of the leg and the pressure in the capillary network. During standing without skeletal-muscle activity, venous pressures in the legs are determined by the hydrostatic component and capillary flow, Skeletal-muscle contractions, as during ambulation, transiently increase pressure within the deep leg veins.
Changes in Venous Valves
Venous valve incompetence is central to the venous hypertension that appears to underlie most or all signs of chronic venous disease. Alterations in and damage to valves have been noted on examination with an angioscope, a fiberoptic catheter that allows clinicians to view the interior of a blood vessel. These changes include stretching, splitting, tearing, thinning, and adhesion of valve leaflets.27 A reduction in the number of valves per unit length has been observed in segments of saphenous veins from patients with chronic venous insufficiency.28 An important step forward came when Ono et al.29 found infiltration of valve leaflets and the venous wall by monocytes and macrophages in all vein specimens from patients with chronic venous disease and in no specimens from controls. Infiltration was associated with areas of endothelium that expressed intercellular adhesion molecule 1 (ICAM-1).
Structural changes
Histologic and ultrastructural studies of varicose saphenous veins have found hypertrophy of the vein wall with increased collagen content,31 together with disruption of the orderly arrangements of smooth-muscle cells and elastin fibers.32,33 Cultures of smooth-muscle cells from varicose saphenous veins have disturbed collagen synthesis, resulting in overproduction of collagen type I and reduced synthesis of collagen type III.
Degradation of extracellular matrix proteins is caused by an array of proteolytic enzymes, including matrix metalloproteinases (MMPs) and serine proteinases, which are produced by vascular cells and inflammatory cells such as macrophages.35 MMPs are released as inactive proenzymes that are activated by other proteinases, including those produced by mast cells,36,37 whereas tissue inhibitors of MMPs (TIMPs) reduce MMP activity. In varicose veins, ratios of TIMP-1 to MMP-2 and TIMP-2 to MMP-2 have been found to be 3.6 times and 2.1 times, respectively, those in veins of control subjects.
In rats, production of an arteriovenous fistula between the femoral artery and vein abruptly increased the pressure in the femoral vein to approximately 90 mm Hg.43-45 Although the valves were stretched immediately by the increased pressure, reflux did not occur until at least two days later and then increased with time. After three weeks, the numbers of granulocytes, monocytes, macrophages, and lymphocytes were increased in the pressurized valves, and MMP-2 and MMP-9 levels were raised. Morphologic changes in the valves also occurred; there were reductions in leaflet height and width, and some valves disappeared. These studies suggest that valves can tolerate high pressures for limited periods, but when there is prolonged pressure-induced inflammation, valve remodeling and loss and reflux occur.
Venous valves are operated by pressure rather than by flow-driven devices, so that little or no reflux is needed to bring about complete closure of the valve.
Physiology
Venous flow is normally pulsatile; venous valves open and close approximately 20 times per minute while a person is standing. When the valve leaflets are fully open, they do not touch the sinus wall (Fig. 3). Flow through the valve separates into a proximally directed jet and a vortical flow into the sinus pocket behind the valve cusp; the vortical flow prevents stasis in the pocket and ensures that all surfaces of the valve are exposed to shear stress. Valve closure occurs when the pressure caused by the vertical flow exceeds the pressure on the luminal side of the valve leaflet because of the proximally directed jet. Interestingly, foot movements, which increase the velocity of the jet, reduce the pressure on the luminal side of the valve leaflets and cause closure of the valve. Thus, minimal reflux occurs and endothelial surfaces are not generally exposed to reverse blood flow.
reactions.
Skin changes
An increase in the occurrence of leg ulceration with increasing postexercise venous pressure was also observed in patients with chronic venous disease; the changes ranged from 0 percent venous ulceration in patients with postexercise venous pressures of less than 30 mm Hg up to 100 percent in patients with postexercise venous pressures of more than 90 mm Hg.
Basal plasma levels of the adhesion molecules ICAM-1, endothelial leukocyte-adhesion
molecule 1, and vascular-cell adhesion molecule 1 were higher in patients with chronic venous disease than in control subjects, and increased significantly in response to venous hypertension provoked by standing.
Unrestrained MMP activity may contribute to the breakdown of the extracellular matrix,
which promotes the formation of ulcers and impairs healing.
In lipodermatosclerosis, the skin capillaries are elongated and tortuous,81 and they may take
on a glomerular appearance, with proliferation of the capillary endothelium in more advanced
cases. Furthermore, plasma VEGF levels were higher in patients with chronic venous disease
with skin changes than in such patients with normal skin.
Another feature of the skin changes associated with chronic venous disease is dermal tissue fibrosis. TGF-β1 is a fibrogenic cytokine.
The hyperpigmentation of skin in lipodermatosclerosis may not be just an innocent by-product
of capillary hyperpermeability. The extravasation of red cells leads to elevated levels of ferritin and ferric iron in affected skin.88,89 These increases may cause oxidative stress, MMP activation, and the development of a microenvironment that exacerbates tissue damage and delays healing.
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