Risk factors and possible therapeutic options to delay the progression of chronic venous disease



Marc VUYLSTEKE, MD, PhD

Vascular Surgeon, Sint-Andriesziekenhuis Tielt, BELGIUM

Address for correspondence: Marc E. Vuylsteke, MD, PhD, Department of Vascular Surgery Sint-Andriesziekenhuis, Bruggestraat 85, 8700 Tielt, Belgium (email: marc.vuylsteke@me.com)

 

Abstract

Chronic venous disease (CVD) is a very common and progressive disease. This means that untreated patients will develop more signs and symptoms of CVD, and this will have an impact on their health-related quality of life (HRQOL). The underlying mechanism of this progression is persistent venous hypertension and local inflammation of the vessel wall. Epidemiological data show the important influence of risk factors on the progression of CVD. Some risk factors, which are mostly lifestyle related, can be influenced. Unfortunately, however, the most important risk factors — such as having a positive family history, age, and sex — are not modifiable. Treating patients with compression and medication does have a positive influence on the symptomatology of CVD and on ulcer healing. Interventional treatment, either surgical or endovenous, does have an important impact on the venous disease. Signs and symptoms will diminish and the patients’ HRQOL will improve significantly. Unfortunately, this will be temporary, as recurrence can be expected. One of the major causes of recurrence is progression of the disease. There is no evidence at present that early intervention has an impact on the underlying progression of CVD.

Introduction

Chronic venous disease (CVD) is a very common disorder in Western societies1,4 and even worldwide.5 estimates of its prevalence vary depending on the population, selection criteria, disease definition, and imaging techniques used. its severity changes dynamically within the adult population. The age-stratified prevalence of truncal varicose veins measured in the edinburgh Vein study was 11.5% in the 18-to-24–year age group, increasing to 55.7% in the 55-to-64–year age group.2-4,6
 
In order to report more precisely on the extent of venous disease, the CeAP classification was introduced in 19947 and updated in 2004.8 This classification is based on clinical manifestations (C), etiological factors (e), anatomic distribution of disease (A), and underlying pathophysiological findings (P).
 
According to the results of the Vein Consult Program, the prevalence of CVD (C1-C6) and chronic venous insufficiency (CVi, C3-C6) are respectively 63.7% and 25.9% worldwide.5 increasing age results in a higher C-classification, with more symptoms and a lower disease-related quality of life (QOl).9 Venous disease is a progressive disease, which means that if untreated, the disease will become more extensive, resulting in more signs and symptoms. it has been shown that progression to a higher clinical stage takes place in 4% of cases per year.10 Half of patients with unilateral varicosities will develop contralateral varicose veins within 5 years.11 One-third of patients with varicose veins will develop skin changes over 13 years.12 Patients with segmental saphenous vein reflux will progress to multisegmental reflux.13
 
Clinical progression of CVD is accompanied by progression of reflux in the superficial veins, and both clinical progression and progression of superficial venous reflux are significantly correlated with age.9,14 The underlying pathophysiology is persistent venous hypertension and a local inflammatory process. These are significantly influenced by other risk factors, such as obesity, orthostatism, (lack of) regular exercise, pregnancy, smoking, having a positive family history (genetics?), and female sex. So, what can we do to delay this progression?
 

Risk factor assessment

The most important risk factors include having a positive family history for venous disease, obesity, age, and sex, and these do have an important influence on the predicted probability of having CVD (all P<0.001).5,9
 
Having a positive family history of CVD is the most common risk factor. The expected risk of developing venous disease is about 90% if both parents are affected. if only one parent is affected, the risk drops to 25% in males and to 62% in females.15 The heritability of CVD is high, which suggests a notable genetic component in the etiology of the disease. To date, no specific gene loci associated with the development of varicose veins have been identified, although mutations in the FOXC2 gene (encoding forkhead box protein C2) are strongly associated with primary valve failure in lower limb veins.16 In any case, there is no way of altering this risk factor. But family history may remain important even if genetic variants are elucidated, because it also reflects interactions between genetic and environmental risk factors.17,18 Family members may have common habits and may be exposed to similar environmental risks.
 
The estimated probabilities for having CVD and CVi for each sex increase with age.9,1419,22 Older age means an increased number of insufficient venous segments and increased risk of clinical progression of CVD from varicose veins to CVi. The pathogenesis of CVD and the influence of age are still debated. Although most experts agree that valve reflux is the principal determinant of varicose veins and CVD, there is no consensus as to whether primary valve incompetence is the initiating event in the pathogenesis of venous disease or whether the incompetence is secondary to vein wall dilatation.323 Some evidence indicates that reflux likely occurs due to weakening of vein walls and subsequent venous dilatation, resulting in incompetence of the valve.24 In varicose veins, the vein wall is highly heterogeneous and can be separated into hypertrophic and atrophic areas. The hypertrophic areas, containing dedifferentiated smooth muscle cells and increased extracellular matrix content, are the result of a “wound-healing” response. The atrophic segments may represent a final stage in the evolution of hypertrophic segments in which the smooth muscle cells have degenerated and disappeared.25
 
One histological study showed that total collagen content and, particularly, intimal collagen decrease with advancing age. Furthermore, the collagen fiber types demonstrated a statistically significant alteration with age.26 The compliance of the venous vessel wall decreases, and it becomes incapable of elastic expansion to cope with changes in blood volume and flow.27 The age-associated decrease in both collagen and elastin may ultimately contribute to an age-associated decrease in venous compliance, leading to an increased risk of venous diseases such as CVD and varicose veins.
 
Degeneration of the vein wall is associated with a local inflammatory reaction. Vein wall degeneration results in modification of local shear stress. local venous hypertension also causes some hypoxia of the vein wall. This triggers the local inflammatory reaction resulting in leukocyte activation and local release of inflammatory regulators. endothelial destruction results from leukocyte attachment. This increases capillary permeability, again leading to release of free radicals and matrix metalloproteases (MMPs). Further degradation of extracellular matrix and destruction of valve leaflets and vein wall structure again leads to increased venous hypertension. This is a continuous self-exacerbating and ongoing process affecting the vein wall, which is altered with age.28,29
 
Age-related degeneration is of course not modifiable, but some medication can decrease the local inflammatory reaction, resulting in improved venous tone.29,30 This is associated with a decrease in symptomatology and edema among the patients with CVD. However, the question of whether these venotonic drugs really have a significant influence on the progression of the venous disease remains unresolved.31
 
Female sex is, in most epidemiological studies, also associated with an increased prevalence of CVD.9 Although evidence is not consistent,2 pregnancy is presumed to be a major contributory factor in the increased incidence of varicose veins.32 Pregnancy is associated with a number of physiological changes that contribute to the development of venous distention and thus, potentially, to varicose veins.33 There is a significant increase in blood volume, caused primarily by plasma volume expansion.3 in addition, fetal growth and weight gain increase intra-abdominal pressure and impair venous return.33,34 Hormonal changes, such as increases in relaxin and progesterone levels, will also weaken the blood vessel wall and have a vasodilator effect.34 This increases the pressure on the venous valves in the lower limbs.
 
Interestingly, one study found a significant difference when comparing male patients with female patients who had never become pregnant. Those female patients had a significantly larger number of symptoms (all female patients) and a higher C-classification (in age groups <50 years) than male patients. This means that pregnancies are not the only reason why female patients have a higher CVD severity on average. genetic factors and hormone state probably play an important part as well.   Obesity has been associated with a more advanced clinical stage of venous disease than observed in nonobese people. This can be explained by increased intra-abdominal pressure, which creates a relative obstruction to centripetal venous flow.35 This leads to venous hypertension and increased risk of CVD progression.
 
Many obese patients also have right cardiac failure, which impairs venous return. However, in severely obese patients, approximately two-thirds of limbs have no anatomic evidence of venous disease.36 The association of increasing limb symptoms with increasing obesity suggests that the obesity itself contributes to the morbidity.
 
On average, obese patients also take less regular exercise and sit down for longer periods, which contributes to venous hypertension. interestingly, edema and skin changes decrease after bariatric surgery.37 This suggests that correcting obesity can have an influence on the progression of venous disease. Cross-sectional epidemiological studies3,5,6,9,20-22 show that risk factors such as prolonged orthostatism and lack of regular exercise are correlated with a higher C-classification. This can be explained by a decreased calf pump function, which increases venous pressure and thus impairs venous flow. Smoking, particularly in males, may also be associated with a higher risk of developing CVD.5 These behavioral factors can be modified and could have a positive effect on the progression of the venous disease. However, more longitudinal studies are necessary to prove that effect.
 

Compression

Compression is widely used in the treatment of venous disease. it improves venous pump function and enhances venous flow velocities. At various stages, compression significantly reduces symptoms and has a positive effect on patients health-related QOl (HRQOl).38,39 Unfortunately, there is insufficient information from randomized trials on the prevention of CVD progression by compression. However, in one study by Kostas et al,11 it was shown that patients adherent to compression therapy experienced slower progression of their CVD than those who did not adhere to such therapy. More studies including large cohorts of patients and long followup periods are necessary to make any final conclusions on the effect of compression on the progression of CVD.
 

Medical therapy

Persistent venous hypertension is widely accepted to be the predominant cause of the progression of CVD. This is accompanied by a local inflammatory reaction in the vein wall and valve leaflets. This is a self-sustaining reaction leading to progressive leaflet destruction and scarring of the vein wall. it has been shown that medical therapy using micronized purified flavonoid fractions (MPFF), reduces this inflammation. These venotonics reduce expression of adhesion molecules, reduce adhesion of leukocytes to the endothelium, and decrease capillary permeability.29,30
 
One study in which patients were treated at an early stage of venous disease (C0s) showed that MPFF is able to reverse transient segmental reflux in the GSV. This resulted in a reduction in symptoms in the affected patients.31 However, more double-blind, randomized controlled clinical trials with long follow-up are necessary before any final conclusions can be reached on the effect of medical therapy on the progression of venous disease. Meanwhile, venotonic drugs should only be considered as a treatment option for swelling and pain caused by CVD.40
 

Interventional therapy

Varicose vein surgery is among the most commonly performed medical interventions and accounts for 1.5% to 2% of total health care expenditure.41 A large proportion of patients looking for interventional treatment are C2 patients, with signs and symptoms of venous disease but without edema or skin changes. Patients with mainly cosmetic problems also request interventions. Due to the prevalence of venous disease, rationing may be necessary.42 Offering treatment only to patients with features of more advanced disease, such as skin changes and ulceration, can reduce the number of patients listed for treatment. However, a certain number of patients with early stage venous disease (C2) will progress to a higher clinical stage (see introduction). untreated patients will develop more signs and symptoms, which has an impact on patients’ HRQOl.43 unfortunately, it is difficult to predict which patients will progress to the higher clinical stages. HRQOl studies show that venous disease does have a significant influence on patients’ QOl, independent of the CeAP clinical classification.44 Results from a randomized trial have also shown that surgery for uncomplicated varicose veins gives a significant benefit over conservative treatment in terms of HRQOl, health status, and patient satisfaction at a relatively small cost.45,46 Therefore, patients with varicose veins with CVi (C3C6), as well as those C2 patients with severe clinical symptoms and impaired QOl due to CVD, should be treated with ablation of the varicose veins in a refunded care system.10
 
Varicose vein surgery does have a positive influence on the signs and symptoms, decreases the clinical C-classification, and improves HRQOl.47,48 However, can varicose vein surgery prevent extension of venous incompetence over time?
 
The reduction in venous hypertension by surgery or endovenous techniques is considered the mainstay of therapy for the treatment of CVD and for avoiding recurrences. experience has taught us that patients treated at an advanced stage, with huge amounts of tributaries, do have more postoperative pain and complaints than those treated in an early stage. They have more postoperative hematomas, induration, pain, and hyperpigmentation.
 
There are, unfortunately, no data available showing any difference in recurrence rates between patients treated in an early stage compared with those treated in an advanced stage of venous disease. independent of the clinical severity of the patient treated, recurrence can be expected in 40% to 50% at 5 years and 70% at 10 years.49,50These recurrences are multifactorial, but progression of the disease should account for 20% to 50% of all recurrences. This may be due to anatomic extension of previous incompetent truncal segments, reflux in new segments, or a combination of both. Varicose vein reflux can develop in any vein, with or without an apparent feeding source.51,52
 
Neovascularization is also a major cause of the recurrence of reflux. At 5 years, it is found in 32% and 50% of cases at the saphenofemoral and saphenopopliteal junctions, respectively.49,53
Many theories exist explaining the underlying cause of neovascularization as a cause of recurrence. One interesting theory is the hemodynamic paradox proposed by C Recek.54 After elimination of the incompetent truncal vein and the tributaries, some small communicating channels might persist. Due to a pressure difference between the femoral vein and the remaining veins in the saphenous system in the thigh during calf pump activity, these minor channels may grow and develop into tortuous dilated veins. The pressure difference increases flow and enhances fluid shear stress on the endothelium in preexisting minor communicating channels between the femoral vein and the saphenous system in the thigh, which triggers release of the biochemical agents nitric oxide and vascular endothelial growth factor; the consequence is enlargement (vascular remodeling) of the communicating channels and, ultimately, reflux recurrence. Hence, the abolition of saphenous reflux creates the conditions for the recurrence of the previous pathological situation.54
 
in a study on the efficacy of surgery of the superficial venous system and compression at early stages of CVD for the prevention of chronic venous ulceration, no difference in terms of avoiding recurrences of ulcerations could be found between patients who were adherent to treatment and those who were not.55 it appears that interventions have no effect on the natural progression toward higher C-classifications.
 

Conclusions

CVD is a progressive disease. its progression is influenced by risk factors. Some risk factors, especially lifestyle-correlated ones such as obesity, smoking, orthostatism, and lack of regular exercise can be influenced, whereas others cannot. early interventions will have a positive influence on patients’ signs and symptoms of CVD and their HRQOl. This positive effect will be temporary. in the meantime, patients will feel better until recurrence occurs. unfortunately, there is no evidence that intervention can delay the underlying progression of CVD.

 

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