1 Department of Prevention Epidaure, CRLC Val d'AurellePaul Lamarque, Montpellier, France.
2 Division of Phlebology, Laboratoires Knoll France, Rungis, France.
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ABSTRACT |
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case-control studies; leg; risk factors; smoking; tobacco; venous insufficiency
Abbreviations: OR, odds ratio; SD, standard deviation
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INTRODUCTION |
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Evaluation of the prevalence of lower limb venous insufficiency varies greatly in the studies, from 15 percent to more than 50 percent, according to sample selection as well as the signs and symptoms collected (14
). Nevertheless, lower limb venous insufficiency clearly is a major public health problem (1
, 4
, 5
), but only a few studies have been carried out to identify preventable risk factors.
The most reliably documented risk factors found in the literature are family history of lower limb venous insufficiency, female gender, older age, obesity, prolonged standing, and full-term pregnancies (1, 4
). Factors such as oral contraceptive use and smoking have been no more than presumptive elements in these studies.
Although the possible role of smoking has already been identified in varicose pathogenesis in the Framingham study (6), no data clearly demonstrate whether tobacco smoking is a risk factor of lower limb venous insufficiency. Besides, it is accepted that smoking is a major factor in oxidative stress (7
), hypoxia through carbon monoxide and nitric oxide fixation to hemoglobin (8
, 9
), and endothelial damage (10
). Among the numerous physiopathologic mechanisms involved in the development of lower limb venous insufficiency, hypoxia related to the closing of precapillary sphincters has been mentioned (11
). This hypoxia would produce a local inflammation increasing vascular permeability and inducing edema. Cellular and molecular mechanisms leading to tissue damage are uncertain; endothelial cells, leukocytes, and release of reactive oxygen might be involved (1
).
In view of the clinical and physiopathogenic presumptions as well as the increase in tobacco smoking over the last few decades (mainly in women) (12), we conducted a case-control study to evaluate the possible association between tobacco smoking and lower limb venous insufficiency.
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MATERIALS AND METHODS |
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Cases were subjects aged between 25 and 65 years who were seeking care from a general practitioner and presenting clinically diagnosed lower limb venous insufficiency (class 1, 2, or 3 of the Ad Hoc Committee classification on reporting standards (13)), characterized by at least two functional symptoms (lower limb pain, heaviness, paresthesia/restless legs and leg cramps evaluated according to a four-level verbal scale (none, slight, moderate, severe), and discomfort with a 10-cm visual analog scale) and one objective sign (skin hyperpigmentation in the gaiter area, end-of-day or permanent venous edema, varicosities, saphenous varicose veins, and/or superficial subcutaneous varicose veins determined by clinical examination) of the disease, or subjects presenting isolated varicose veins. Each physician had to make a special clinical examination of the lower limbs and to report the data on the questionnaires (inclusion criteria), using Ad Hoc Committee classification. This information was gathered during the consultation.
Each general practitioner included prospectively the first four eligible patients (one woman under age 45 years, two women over age 45 years, and one man) during the recruitment period.
Each control was the next eligible matched patient following the case, consulting for a medical act, such as vaccination, medical certificate, or health monitoring, or for an illness with no relation to lower limb venous insufficiency, after questioning and physical examination.
Gender and age (4, 6
) are two factors considered to play an important role in the development of lower limb venous insufficiency, as well as in prevalence of tobacco smoking (12
). In order to eliminate these confounding factors, cases and controls were matched by gender in 10-year age groups.
Exclusion criteria for the entire group of cases and controls included current or recent pregnancy (<3 months) for women; edema from general, therapeutic, or traumatic causes; established heart, kidney, or liver failure; severe respiratory impairment or chronic bronchitis; pure or postoperative lymphatic insufficiency; arterial or arteriovenous lesions of the lower limbs; diabetes; and cancer or other diseases potentially leading to veinolymphatic side effects in the lower limbs.
Study design
A questionnaire administered by the clinician himself was designed to gather information on the reason for consultation, general characteristics of the subject (body mass index, occupational status, standing time (>4 hours/day)), smoking habits (14, 15
), alcohol consumption (
80 g/day in men and
40 g/day in women) with or without clinical signs of alcohol abuse (tremor, breath, verbal confusion, bloodshot conjunctiva, violent reaction to aggressions, hyperreflexivity, loss of balance, loss of memory), and known risk factors of lower limb venous insufficiency (family history of venous insufficiency, physical activity, heat exposure (hot bath, sauna, Turkish bath), and (for women) number of pregnancies, use of oral contraceptives, and menopause). The subject's routine medical treatments were noted, allowing for verification of the exclusion criteria. The therapeutic strategy used to treat lower limb venous insufficiency was also noted.
The study was approved by the Conseil National de l'Ordre des Médecins and Comité National Informatique et Liberté. Each subject had to receive information on the study before consenting to participate. Data verification procedures were implemented during all steps of the data collection process.
Statistical analysis
Sample size calculations were based on the age-gender dependence of smoking prevalence (48 percent for men and 35 percent for women under 45 years of age; 10 percent for women 45 years or older (12)). A relative risk level of
1.5 was chosen because this level of risk for varicose veins was shown in the Framingham study for male smokers (6
). With 80 percent power and
= 0.05, the study needed to recruit 800 women under the age of 45 years, 1,800 women aged 45 years or older, and 770 men (i.e., 1,685 cases and 1,685 controls).
Characteristics of cases and controls were compared using 2 tests for discrete variables, and Student's t tests were used for continuous variables. In univariate analysis, the crude odds ratios and their 95 percent confidence intervals were calculated for each variable.
A multivariate analysis was performed by introducing the variables found significant in univariate analysis (p 0.10) using a conditional logistic regression model on all subjects, for men and for women younger and older than age 45 years.
For variables related to smoking, forward stepwise logistic regression was used for entering variables in order to select the most significant ones. Missing data were imputed by a linear regression technique of the variables found significant in the multivariate analysis on the complete data set (16). Adjusted odds ratios for the final model were calculated using nonsmokers as the reference category. The interaction terms of each significant variable in the final model and age groups did not significantly improve the model.
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RESULTS |
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The average age for cases and controls was similar: 48 (standard deviation (SD), 10) years. The proportion of subjects under 45 years of age was 36 percent for women and 30 percent for men.
Characteristics for venous disorders for the cases showed a significant difference in the clinical symptoms of the disease between men and women (table 1). In women, disease onset occurred at an earlier age than in men (28.3 (SD, 11) years vs. 32.4 (SD, 13) years; p < 0.001), and symptoms were more often bilateral (89 percent vs. 77 percent), with more severe pain (11 percent vs. 7 percent) and more permanent pain (30 percent vs. 23 percent). In addition, women suffered from less intense cramps than did men (8 percent vs. 11 percent) but more frequently from severe sensations of heaviness (29 percent vs. 23 percent) and greater discomfort (5.6 (SD, 1.7) cm vs. 5.4 (SD, 1.7) cm on the visual analog scale; p = 0.009). Moreover, the objective signs recorded showed more varicosities (89 percent vs. 77 percent) and edema (76 percent vs. 65 percent) in women, while men presented more frequently with varicose veins (86 percent vs. 70 percent) as well as trophic disorders (18 percent vs. 13 percent) with skin hyperpigmentation (37 percent vs. 27 percent).
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Comparison between cases and controls
Comparison of cases and controls for general characteristics showed that the mean body mass index for patients with lower limb venous insufficiency (24.7 (SD, 4.2) kg/m2) was significantly greater than that of controls (23.9 (SD, 3.5) kg/m2; p < 0.001) (table 2). The distribution of professional activity was similar between cases and controls.
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Investigation of smoking habits brought out a higher proportion of smokers (crude OR = 2.2) and former smokers (crude OR = 1.6) in cases than in controls. The results, moreover, showed a significantly higher proportion of cases who smoked dark tobacco (crude OR = 2.8), inhaled smoke (crude OR = 2.2), smoked unfiltered cigarettes (crude OR = 3.2), or smoked more than 19 cigarettes a day (crude OR = 3.0) compared with the controls. Cases began smoking at an earlier age (19.8 (SD, 4.6) years vs. 20.8 (SD, 4.9) years; p < 0.001), and the number of smoking years (22.1 (SD, 9.3) years vs. 19.9 (SD, 9.8) years; p < 0.001) was also significantly higher. Former smoker cases stopped smoking at a later age as opposed to their control counterparts (41.3 (SD, 10.2) years vs. 38.6 (SD, 10.7) years; p < 0.01).
Multivariate analysis (table 2) confirmed that family history of lower limb venous insufficiency, frequent and regular on-the-job standing, and regular exposure to heat were significant risk factors. On the other hand, sports activity and an active lifestyle were more frequent in controls than in cases. In addition, smokers and former smokers were more frequently present as cases.
Comparison by gender
In men (table 3), the general model risk factors were reproduced: family history, frequent or regular standing, exposure to heat, and number of cigarettes/day. However, the apparent protective effect of physical activity was no longer significant.
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The conditional logistic regression carried out on the population of women aged 45 years or over also showed, as in the overall model for women, that family history (adjusted OR = 10.6, 95 percent confidence interval: 6.9, 16.3), regular standing (adjusted OR = 1.9, 95 percent confidence interval: 1.2, 3.1), and number of cigarettes smoked per day (adjusted OR = 1.8 for 1019 cigarettes/day, 95 percent confidence interval: 1.1, 2.9; adjusted OR = 2.0 for >19 cigarettes/day, 95 percent confidence interval: 1.0, 4.0) were lower limb venous insufficiency risk factors. Physical activity was also protective (adjusted OR = 0.7 for active lifestyle, 95 percent confidence interval: 0.5, 1.0; adjusted OR = 0.3 for sports activity, 95 percent confidence interval: 0.1, 0.9). However, the association with the number of pregnancies did not appear in this population.
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DISCUSSION |
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In terms of smoking habits, recall bias is rare. Moreover, we found a significant association among all the smoking characteristics that increase smokers' risk of other diseases: a dose effect, a duration effect, a filter effect, a smoke inhalation effect, and a dark tobacco effect (table 2). This is difficult to explain by a potential tendency of cases to declare themselves smokers and/or heavier smokers more often than did controls because of their lower limb venous insufficiency. In addition, the physicians who questioned cases and controls were randomly selected and therefore are not a group particularly sensitive to the damaging effects of tobacco in lower limb venous insufficiency.
The cases appeared to be representative of patients with lower limb venous insufficiency in terms of both clinical aspects and known risk factors (table 1). Functional symptomatology, varicosities, and edema were more frequently reported in women than in men. However, varicose veins and trophic disorders were significantly more frequent in men. In the Basel study (2), as well as the Edinburgh survey (17
), and in Isaaks' case-control study of lower limb venous insufficiency symptomatology (18
), a similar difference for gender was found with functional symptoms 1.7 times more frequent in women than in men (18
). Thus, misclassification for cases does not seem to have occurred. It is possible that a few asymptomatic cases were classified as controls, but this would only decrease the difference we already found.
Comparison of the disease's severity by age group showed its progress with age: More severe symptoms and more frequent trophic disorders, which are important signs of severe lower limb venous insufficiency (19), were observed in the oldest age group (5565 years). In the study by Capitao et al. (20
), age also appeared clearly as a factor of severity in lower limb venous insufficiency.
In addition, the other previously recognized risk factors of lower limb venous insufficiency (3, 6
) were found with a statistically significant difference for family history, excess body mass index, and prolonged standing. It should be noted that the proportions of overweight and obese patients were noticeably high in the case group, particularly among former smokers; a weight gain due to smoking cessation (21
) could explain this proportion in former smokers.
Although the use of oral contraceptives has been associated with increased risk of deep vein thrombosis (22), the association between oral contraceptives and superficial lower limb venous insufficiency is not so clear. For instance, the study by Capitao et al. (20
) showed no linear correlation with the severity of lower limb venous insufficiency in women receiving estrogen treatment but a linear trend between the disease's severity and the use of high-dose estrogen. Moreover, Scott et al. (23
), in a case-control study comparing 129 patients with varicose veins and 93 patients with venous ulcers with 113 hospital control patients, observed no relation with current oral contraceptive use. In our study, we found no association between oral contraceptive use and lower limb venous insufficiency although the statistical power is high, considering the prevalence of contraceptive use.
The mechanisms responsible for the harmful effects of tobacco on the venous system are still not elucidated. However, cigarette smoking is known to be a major factor in hypoxia through fixation of carbon monoxide and nitric oxide to hemoglobin (810
).
Otherwise, among the numerous physiopathologic mechanisms involved in the development of lower limb venous insufficiency, the relation between hypoxia and precapillary closure of sphincters, itself related to venous hyperpressure, has been pointed out (11). Some authors hypothesized that hypoxia activates the endothelial cells, leading to the production of proinflammatory factors within the vessel wall and resulting in increased capillary permeability and local inflammatory changes (24
). Moreover, in patients suffering from lower limb venous insufficiency, a proliferation of smooth muscle cells in the venous walls has been observed with a parallel disorganization and a loss of elasticity (25
).
In smokers, biochemical modifications have been observed on the venous endothelium (26, 27
). According to Higman et al. (26
), these modifications could induce an increase in vasomotor tonicity and smooth muscle proliferation. These reactions could explain changes in the venous walls favoring the occurrence of varicose veins. Furthermore, Dovgan et al. (28
) demonstrated that the adherence of human monocytes to human endothelial cells of the cultured umbilical vein was significantly increased in smokers, with the increase proportional to tobacco smoking. Smoking is also responsible for lengthening scarring time (29
), which could have a harmful effect on the trophic disorders associated with chronic lower limb venous insufficiency.
Another hypothesis, evoked in atherosclerosis pathogenesis in smokers, also deserves further studies in patients with lower limb venous insufficiency. It has been assumed that the many harmful effects of tobacco smoke would be due to both direct oxidative damage to critical biologic substances and activation of phagocytic cells that, in turn, would generate highly reactive oxygen species (7, 30
, 31
). Production of free radicals could thus contribute to the endothelial damage and local inflammation responsible for microvascular disorders that occur in venous insufficiency.
In conclusion, venous insufficiency is significantly associated with tobacco smoking after adjustment for other risk factors. This association was found for men as well as for women, in both age groups. To our knowledge, the Framingham study (6) is the only other epidemiologic study that found that varicose veins coexisted with higher smoking rates for men. However, this study did not find this association for women.
The present study does not seem to contain major biases that would invalidate the results. It suggests that smoking increases the risk of lower limb venous insufficiency with a dose-effect relation. This relation between tobacco smoking and lower limb venous insufficiency should be taken into account given that the biologic data reasonably support the underlying physiopathologic mechanisms.
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ACKNOWLEDGMENTS |
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The authors thank all the general practitioners who provided the patients for this study and also the members of the scientific committee: Professor G. Lagrue (Department of Tabacology, Hôpital Henri Mondor, Créteil, France), Dr. J.-M. Coget (Lille, France), Dr. G. Zemmour (Paris, France), and Dr. G. Mayer (Paris, France) for their scientific and medical contributions.
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NOTES |
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REFERENCES |
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