Digestive Diseases and Sciences, Vol. 36, No. 8 (August 1991), pp. 1147-1150
Smoking, the Oral Contraceptive Pill, and Crohn's Disease A.J. WAKEFIELD, FRCS, A.M. SAWYERR, MRCP, M. HUDSON, MRCP, A.P. DHILLON, FRCPath, and R.E. POUNDER, FRCP
Both cigarette smoking and the oral contraceptive pill have been implicated as aggravating factors in Crohn's disease. Based upon the recent demonstration of multifocal gastrointestinal infarction in Crohn' s disease, a possible pathogenic mechanism for this condition, we propose how smoking and the oral contraceptive pill may potentiate a tendency f or focal thrombosis and hence exacerbate the activity of Crohn's disease. KEY WORDS: Crohn's disease; procoagulant activity; smoking; oral contraceptive.
There is a growing body of evidence that consistently links cigarette smoking to Crohn's disease (I-10). In particular, individuals with Crohn's disease who smoke have been reported to experience statistically significantly more relapses, hospital admissions, surgery, pain, diarrhea and changes in white cell count than nonsmokers with Crohn's disease, suggesting that smoking activates the disease (5). The evidence for a potentiating effect of the oral contraceptive pill on Crohn's disease, although less well defined than that for smoking, has been implicated in several studies (11-16). Moreover, discontinuation of the pill has led to a sustained improvement of disease activity in a number of patients (11-16). An understanding of the mechanism by which these two influences potentially exacerbate Crohn's disease may provide a further insight into the pathogenesis of this condition and may have important implications for the introduction of new therapeutic modalities in Crohn's disease. Manuscript received April 16, 1990; accepted May 24, 1990. From the Inflammatory Bowel Disease Study Group, Academic Departments of Medicine and Histopathology, Royal Free Hospital School of Medicine, London NW3 2QG, England. Address for reprint requests: Mr. A.J. Wakefield, FRCS, Academic Department of Medicine, Royal Free Hospital School of Medicine, Pond Street, London, NW3 2QG, England.
MULTIFOCAL GASTROINTESTINAL INFARCTION AND PROCOAGULANT ACTIVITY We have recently proposed a pathogenic mechanism for Crohn's disease, multifocal gastrointestinal infarction, which is mediated by a chronic mesenteric vasculitis (17). Focal vascular injury is confined to intramural vessels supplying segments of intestine affected by Crohn's disease, and it is characterised initially by fibrin deposition at the focus of monocyte adherence to endothelium. Advanced lesions consist of a chronic inflammatory cell infiltrate in the blood vessel wall with necrosis of the vessel wall and thrombosis of the affected vessel. It is likely that enhanced expression of both monocyte and vascular endothelial cell procoagulant activity (17, 18) is the initiating event in fibrin formation at the focus of this cellular interaction. Induction of procoagulant expression by these cells is a functional property of Interleukin-1 (ILl), levels of which are elevated in Crohn's disease (19, 20). IL-I, a monocyte/vascular endothelial cell-derived inflammatory cytokine, is capable of profoundly altering the antithrombotic properties of these cells. In addition to inducing the synthesis and expression of tissue factor procoagulant activity (21, 22), IL-I suppresses the anticoagulant
Digestive Diseases and Sciences, Vol. 36, No. 8 (August 1991)
WAKEFIELD ET AL activity of thrombomodulin (23), which is expressed normally by endothelial cells. Furthermore, IL-1 alters the fibrinolytic properties of endothelial cells by decreasing tissue-type plasminogen-activator activity, also reported to be reduced in Crohn's disease (24), and augmenting production of a tissue plasminogen activator inhibitor (25-27). In addition, IL-I increases the endothelial cell production of platelet-activating factor, a potent activator of platelets and leukocytes and a vasoconstrictor (28), levels of which have been reported to be raised in colitis (29). There is evidence to suggest that modulation of IL-1 synthesis, and consequently the maintenance of thromboresistance at the surface of quiescent endothelium, is a functional property of bioactive prostaglandins, derived from arachidonate metabolism via the cyclooxygenase pathway (30, 31). Prostacyclin, a principal arachidonate derivative, is synthesized by endothelial cells at a low rate under normal circumstances. However, perturbation of the endothelium, leading to IL-1 expression, increased procoagulant activity, and local thrombin formation, stimulates endothelial cell prostacyclin synthesis (27). This probably reflects an highly integrated feedback loop, operative at the level of the endothelial cell, that acts to restore the anticoagulant integrity of these cells (32). Prostacyclin is also a powerful inhibitor of platelet aggregation and a vasodilator (33), and thus exerts its effects at multiple levels in the inhibition of focal thrombosis and the maintenance of microvascular perfusion. Evidence for this pivotal role for prostaglandins in the control of intravascular hemostasis has received considerable support from studies in which therapeutic intervention with prostaglandin analogs has produced marked attenuation of procoagulant activity and improvement in clinical condition in diseases in which this pathway is thought to be a principal effector of tissue injury (34, 35). CIGARETTE SMOKING AND PROCOAGULANT ACTIVITY With knowledge that focal activation of intravascular coagulation is a principal feature in the pathogenesis of Crohn's disease, it is possible to propose how both cigarette smoking and the oral contraceptive pill may potentiate this mechanism. Cigarette smoking, a risk factor for atherosclerosis (36, 37), has been shown to induce morphological injury to
endothelial cells. This injury was associated with formation of microthrombi, impaired endothelial cell prostacyclin synthesis, and an enhanced aggregatory capacity of platelets (38). Furthermore chronic infusion of nicotine into rats has been reported to inhibit aortic endothelial prostacyclin synthesis (35). These findings have been substantiated by reports of the inhibition of endothelial cell prostacyclin synthesis by nicotine (35, 39). Furthermore, elevated plasma fibrinogen levels and decreased levels of both plasminogen and tissue plasminogen activator activity have been reported in habitual smokers (40). These findings may explain, at least in part, the increased risk of thrombotic vascular disease in smokers. ORAL CONTRACEPTIVE AND PROCOAGULANT ACTIVITY Although an association between thromboembolic disease and the oral contraceptive pill remains controversial (41), these drugs are able to exert a number of influences upon substrates of coagulation that may enhance a tendency to focal thrombosis in conditions where prior activation of coagulation exists. Estrogens above a dosage level of 50 ~g of ethinylestradiol induce effects in both the coagulation and fibrinolytic enzyme systems (42, 43). There have been a number of reports of increased levels of fibrinogen (42, 43), factors II (prothrombin) (42, 44), VII (a direct substrate for tissue factor activity) (42, 44), VIII, and X (42). Reduced levels of antithrombin III, a circulating anticoagulant that inhibits thrombin activity at the endothelial cell surface, also have been described in users of the pill (42, 46), a finding that also has been reported in association with Crohn's disease (47). In addition, rapid fibrinolysis (42, 48) and decreased levels of vascular endothelial-tissue plasminogen activator (42, 49) have been reported during oral contraceptive use, possibly reflecting enhanced consumption in response to intravascular coagulation. Tissue plasminogen activator activity is reduced in active Crohn's disease (23), possibly as a result of the presence of a monocyte/vascular endothelial cell-derived tissue plasminogen activator inhibitor (26, 50), and this may contribute to a tendency for focal thrombosis in this condition. It is of interest that both changes in indices of coagulation and Crohn's disease activity may undergo sustained improvement following cessation of oral contraceptive therapy (6, 42). Digestive Diseases and Sciences, Vol. 36, No. 8 (August 1991)
SMOKING, THE PILL, AND CROHN'S DISEASE ACTIVATION OF CROHN'S DISEASE We have observed microvascular changes in patients with Crohn's disease who neither smoke nor take oral contraceptives (17). However, it is tempting to suggest that when further prothrombotic stimuli such as oral contraceptives, which contain more than 50 p~g of ethinylestradiol, or cigarette smoking are superimposed upon Crohn's disease, exacerbation of disease activity is the likely outcome. In the case of cigarette smoking, this activation may be due to a direct endothelial cell injury, impaired prostacyclin production, and a decreased fibrinolytic capacity of these cells. With oral contraceptives containing more than 50 ~g of ethinylestradiol, potentiation of thrombosis may result from augmented levels of procoagulant substrates and associated decreases of both anticoagulant and fibrinolytic activity. It is of note that Lashner et al, have recently failed to find an association between oral contraceptives and Crohn's disease (51). However, this study did not gather information on the nature or strength of the oral contraceptive used. In light of the dose-dependent effects of ethinylestradiol on levels of procoagulant substrate and anticoagulant activity (42), this would seem to be crucial information, and thus lack of an association cannot be based on this study alone. Their findings may reflect, in part, the current trend towards prescribing oral contraceptives that contain lower levels of estrogen. CONCLUSION
We are presently investigating the role of the cellular procoagulant pathway in Crohn's disease and will be paying close attention to the activity of this pathway in both smokers and those taking an oral contraceptive. In the meantime, patients who suffer from Crohn's disease should be advised to abstain from smoking and female sufferers should seek expert guidance concerning the type of oral contraceptive they are using. ACKNOWLEDGMENTS We thank Miss Doris Elliott for her help in preparation of this manuscript, the Wellcome Trust for their continued support (Mr. A.J. Wakefield is a Wellcome Research Fellow), and the Crohn's in Childhood Research Appeal.
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Digestive Diseases and Sciences. Vol. 36, No. 8 (August 1991)