Volume Number
124 6
Fatal pulmonary venoocclusive after use of oral contraceptives
Brief Communications
1643
disease
Jonathan N. Townend, MRCP,” David H. Roberts, MD,a E. Lynn Jones, MD,b and Michael K. Davies, MDa Birmingham, England
We describe a young woman with a history of use of oral contraceptive pills in whom the diagnosis of pulmonary venoocclusive diseasewas made only after death. A previously healthy 24-year-old woman presentedwith a 4-month history of progressive dyspnea and fatigue, which had become incapacitating in the week before her admissionto the hospital. There was no history of chest pain or other respiratory symptoms. She had been taking the oral contraceptive pill Trinordiol (levonorgestrel50 to 125 wg,and ethinyl estradiol30 to 40 +g) for a total period of 1 year until 3 months before presentation. During a physical examination she was breathlessat rest and had central cyanosis.Pulsewas 100beats/min, and blood pressurewas95/60 mm Hg. There wasclinical evidenceof right ventricular hypertrophy and auscultation revealed a loud pulmonary component of the second sound but no murmurs The chest was clear, and there was no clinical evidenceof peripheral venousthrombosis.An ECG showed right axis deviation and right ventricular hypertrophy with strain. A chest roentgenogram showed cardiomegaly and proximal pulmonary arterial enlargement, but the lung fields were clear with no Kerley’s B lines or alveolar edema (Fig. 1). Echocardiography revealed right atria1 and ventricular enlargement with no evidence of intracavitary thrombus; pulmonary artery pressurewasmeasuredby Doppler echocardiography at 60 mm Hg above right atria1 pressure. Arterial blood gaseson air revealed a PACOZof 54 mm Hg and a PA@ of 29 mm Hg. Right heart catheterization demonstrated elevated pulmonary artery pressureof 65/30 mm Hg; mean pulmonary artery wedgepressurewasnormal at 10 mm Hg. Pulmonary angiography showeddilatation of the main pulmonary arteries but no evidence of thrombus or segmentalperfusion defects. There appeared to be no delay in emptying of the pulmonary arteries or in filling of the pulmonary veins. Although the pulmonary angiogram wasnot diagnostic, it wasbelieved that thromboembolism could not be excluded as a diagnosis,and intravenous administration of heparin. which had beenstarted at the time of presentation, wascontinued. Two days later the patient collapsedsuddenly, she had no pulse and was apneic. An ECG showedelectromechanicaldissociation.There wasno responseto resuscitative measures;emergencysurgery was From the University of Birmingham, a the Department of Cardiovascular Medicine and bthe Department of Pathology. Reprint requests: Jonathan N. Townend, MRCP, Queen Elizabeth Hospital, Division of Cardiology, Edgbaaton, Birmingham, B15 2TH England. 414141394
Fig. 1. Chest roentgenogramshowing cardiomegaly and proximal pulmonary artery enlargementbut no evidenceof Kerley’s B lines or alveolar edema.
undertaken becauseof a presumptive diagnosisof massive pulmonary embolism,but no thrombus waslocated in the proximal pulmonary arterial system. In spite of intensive mechanicalsupport the patient wasunable to be weaned from bypass. Postmortem examination confirmed dilatation and hypertrophy of the right heart chambers.No thrombus was found in the pulmonary arterial tree, the walls of which were thickened in a manner that is consistentwith pulmonary hypertension. Histologic examination of lung tissue (Fig. 2) revealedmarked narrowing or occlusionof the large and small pulmonary veins by cellular intimal fibrous t,issue. Many of the veins were “arterialized” with marked medial hypertrophy. Muscularization of the pulmonary arterioles wasnoted. The lung parenchyma was congested with intraalveolar and lymphatic edema,patchy interstitial fibrosis, hemosiderosis,and numerousintraalveolar siderophages.The appearancewastypical of pulmonary venoocclusive disease. Pulmonary venoocclusive diseaseis one of a number of rare causesof pulmonary hypertension causedby obstruction to pulmonary venousdrainage. Others include car triatriatum, stenosisof pulmonary veins, and obstructive forms of anomalouspulmonary venousdrainage. The term
1644
Brief Communications
Fig. 2. Two siderophages
large pulmonary are present within
Amercan
December 1992 Heart Journal
veins occluded by loosely cellular intimal fibrous tissue. Numerous the alveoli. (Hematoxylin and eosin stain; original magnification ~312.)
pulmonary venoocclusive disease was introduced by authors from this hospital in 1966,’ although the condition was first described in 1934.2 To date, approximately 100 cases have been reported. There appears to be no single underlying cause; the only strong association is with chemotherapy that is given for treatment of malignant disease.” The condition is usually rapidly fatal, and few patients survive longer than 12 months after diagnosis. No treatment has been shown to be effective, although occasional favorable responses to anticoagulants,4 vasodilators,5 and immunosuppressive agents6 have been reported. Early consideration of heart and lung transplantation therefore seems advisable. This necessitates the rapid differentiation of patients with pulmonary venoocclusive disease from those with primary pulmonary hypertension or recurrent thromboembolism who may have a longer course. Clinically the diagnosis is difficult. The chest roentgenogram may be the most useful investigative tool. In addition to the nonspecific roentgenographic features of pulmonary arterial hypertension, there may be features of pulmonary venous hypertension such as Kerley’s B lines or alveolar edema. However, as our case demonstrates, such findings are not invariable. Measurement of pulmonary artery wedge pressure is unhelpful, because it may be normal or elevated.’ Pulmonary angiography and ventilation perfusion scanning are helpful mainly in excluding the diagnosis of thromboembolism. The diagnosis can only be made unequivocally by means of open lung biopsy. In a report from the National Heart, Lung and Blood Institute,s 7 of 58 (12 CC)patients with primary pulmonary hypertension who had histologic examinations were found to have pulmonary
venoocclusive disease. This case suggests that although the procedure may be hazardous, early open lung biopsy in patients with unexplained severe pulmonary hypertension should be considered. There is substantial evidence that the vascular intimal fibrosis of pulmonary venoocclusive disease is a result of a thrombotic process.g Although thromboembolic disease is a well recognized side effect of the oral contraceptive pill, an association with pulmonary venoocclusive disease has not been reported before. The possibility that the use of oral contraceptives may be an etiologic factor in the development of pulmonary venoocclusive disease should be investigated. REFERENCES
1. Heath D, Segel N, Bishop J. Pulmonary veno-occlusive disease. Circulation 1966;34:242-8. 2. Hora J. Zur Histologie des klinischen ‘primaren Pulmonalsklerose’. Frankf Z Path01 1934;47:100-8. 3. Joselson R, Warnock M. Pulmonary veno-occlusive disease after chemotherapy. Hum Path01 1983;14:88-91. 4. Chawla SK. Kittle CF. Faber LP. Jensik RJ. Pulmonarv venoocclusive’disease. Ann Thorac Surg 1976;22:249-53. ” 5. Salzman GA, Rosa UW. Prolonged survival in pulmonary venoocclusive disease treated with nifedipine. Chest 1989;95:1154-6. 6. Sanderson JE, Spiro SG, Hardry AT, Turner-Warwick M. A case of pulmonary veno-occlusive disease responding to treatment with azathioprine. Thorax 1977;32:140-8. General Hospital (Case 21. 7. Case records of the Massachusetts 1986). N Engl J Med 1986;314:1435-45. of pri8. Pietra GG, Edwards WD, Kay M, et al. Histopathology marypulmonaryhypertension. Circulation1989;80:1198-1206. 9. Wagenvoort. CA, Wagenvoort N, Takahashi T. Pulmonary venoocclusive disease. Involvement of pulmonary arteries and review of the literature. Hum Path01 1985;16:1033-41.
124 6
Fatal pulmonary venoocclusive after use of oral contraceptives
Brief Communications
1643
disease
Jonathan N. Townend, MRCP,” David H. Roberts, MD,a E. Lynn Jones, MD,b and Michael K. Davies, MDa Birmingham, England
We describe a young woman with a history of use of oral contraceptive pills in whom the diagnosis of pulmonary venoocclusive diseasewas made only after death. A previously healthy 24-year-old woman presentedwith a 4-month history of progressive dyspnea and fatigue, which had become incapacitating in the week before her admissionto the hospital. There was no history of chest pain or other respiratory symptoms. She had been taking the oral contraceptive pill Trinordiol (levonorgestrel50 to 125 wg,and ethinyl estradiol30 to 40 +g) for a total period of 1 year until 3 months before presentation. During a physical examination she was breathlessat rest and had central cyanosis.Pulsewas 100beats/min, and blood pressurewas95/60 mm Hg. There wasclinical evidenceof right ventricular hypertrophy and auscultation revealed a loud pulmonary component of the second sound but no murmurs The chest was clear, and there was no clinical evidenceof peripheral venousthrombosis.An ECG showed right axis deviation and right ventricular hypertrophy with strain. A chest roentgenogram showed cardiomegaly and proximal pulmonary arterial enlargement, but the lung fields were clear with no Kerley’s B lines or alveolar edema (Fig. 1). Echocardiography revealed right atria1 and ventricular enlargement with no evidence of intracavitary thrombus; pulmonary artery pressurewasmeasuredby Doppler echocardiography at 60 mm Hg above right atria1 pressure. Arterial blood gaseson air revealed a PACOZof 54 mm Hg and a PA@ of 29 mm Hg. Right heart catheterization demonstrated elevated pulmonary artery pressureof 65/30 mm Hg; mean pulmonary artery wedgepressurewasnormal at 10 mm Hg. Pulmonary angiography showeddilatation of the main pulmonary arteries but no evidence of thrombus or segmentalperfusion defects. There appeared to be no delay in emptying of the pulmonary arteries or in filling of the pulmonary veins. Although the pulmonary angiogram wasnot diagnostic, it wasbelieved that thromboembolism could not be excluded as a diagnosis,and intravenous administration of heparin. which had beenstarted at the time of presentation, wascontinued. Two days later the patient collapsedsuddenly, she had no pulse and was apneic. An ECG showedelectromechanicaldissociation.There wasno responseto resuscitative measures;emergencysurgery was From the University of Birmingham, a the Department of Cardiovascular Medicine and bthe Department of Pathology. Reprint requests: Jonathan N. Townend, MRCP, Queen Elizabeth Hospital, Division of Cardiology, Edgbaaton, Birmingham, B15 2TH England. 414141394
Fig. 1. Chest roentgenogramshowing cardiomegaly and proximal pulmonary artery enlargementbut no evidenceof Kerley’s B lines or alveolar edema.
undertaken becauseof a presumptive diagnosisof massive pulmonary embolism,but no thrombus waslocated in the proximal pulmonary arterial system. In spite of intensive mechanicalsupport the patient wasunable to be weaned from bypass. Postmortem examination confirmed dilatation and hypertrophy of the right heart chambers.No thrombus was found in the pulmonary arterial tree, the walls of which were thickened in a manner that is consistentwith pulmonary hypertension. Histologic examination of lung tissue (Fig. 2) revealedmarked narrowing or occlusionof the large and small pulmonary veins by cellular intimal fibrous t,issue. Many of the veins were “arterialized” with marked medial hypertrophy. Muscularization of the pulmonary arterioles wasnoted. The lung parenchyma was congested with intraalveolar and lymphatic edema,patchy interstitial fibrosis, hemosiderosis,and numerousintraalveolar siderophages.The appearancewastypical of pulmonary venoocclusive disease. Pulmonary venoocclusive diseaseis one of a number of rare causesof pulmonary hypertension causedby obstruction to pulmonary venousdrainage. Others include car triatriatum, stenosisof pulmonary veins, and obstructive forms of anomalouspulmonary venousdrainage. The term
1644
Brief Communications
Fig. 2. Two siderophages
large pulmonary are present within
Amercan
December 1992 Heart Journal
veins occluded by loosely cellular intimal fibrous tissue. Numerous the alveoli. (Hematoxylin and eosin stain; original magnification ~312.)
pulmonary venoocclusive disease was introduced by authors from this hospital in 1966,’ although the condition was first described in 1934.2 To date, approximately 100 cases have been reported. There appears to be no single underlying cause; the only strong association is with chemotherapy that is given for treatment of malignant disease.” The condition is usually rapidly fatal, and few patients survive longer than 12 months after diagnosis. No treatment has been shown to be effective, although occasional favorable responses to anticoagulants,4 vasodilators,5 and immunosuppressive agents6 have been reported. Early consideration of heart and lung transplantation therefore seems advisable. This necessitates the rapid differentiation of patients with pulmonary venoocclusive disease from those with primary pulmonary hypertension or recurrent thromboembolism who may have a longer course. Clinically the diagnosis is difficult. The chest roentgenogram may be the most useful investigative tool. In addition to the nonspecific roentgenographic features of pulmonary arterial hypertension, there may be features of pulmonary venous hypertension such as Kerley’s B lines or alveolar edema. However, as our case demonstrates, such findings are not invariable. Measurement of pulmonary artery wedge pressure is unhelpful, because it may be normal or elevated.’ Pulmonary angiography and ventilation perfusion scanning are helpful mainly in excluding the diagnosis of thromboembolism. The diagnosis can only be made unequivocally by means of open lung biopsy. In a report from the National Heart, Lung and Blood Institute,s 7 of 58 (12 CC)patients with primary pulmonary hypertension who had histologic examinations were found to have pulmonary
venoocclusive disease. This case suggests that although the procedure may be hazardous, early open lung biopsy in patients with unexplained severe pulmonary hypertension should be considered. There is substantial evidence that the vascular intimal fibrosis of pulmonary venoocclusive disease is a result of a thrombotic process.g Although thromboembolic disease is a well recognized side effect of the oral contraceptive pill, an association with pulmonary venoocclusive disease has not been reported before. The possibility that the use of oral contraceptives may be an etiologic factor in the development of pulmonary venoocclusive disease should be investigated. REFERENCES
1. Heath D, Segel N, Bishop J. Pulmonary veno-occlusive disease. Circulation 1966;34:242-8. 2. Hora J. Zur Histologie des klinischen ‘primaren Pulmonalsklerose’. Frankf Z Path01 1934;47:100-8. 3. Joselson R, Warnock M. Pulmonary veno-occlusive disease after chemotherapy. Hum Path01 1983;14:88-91. 4. Chawla SK. Kittle CF. Faber LP. Jensik RJ. Pulmonarv venoocclusive’disease. Ann Thorac Surg 1976;22:249-53. ” 5. Salzman GA, Rosa UW. Prolonged survival in pulmonary venoocclusive disease treated with nifedipine. Chest 1989;95:1154-6. 6. Sanderson JE, Spiro SG, Hardry AT, Turner-Warwick M. A case of pulmonary veno-occlusive disease responding to treatment with azathioprine. Thorax 1977;32:140-8. General Hospital (Case 21. 7. Case records of the Massachusetts 1986). N Engl J Med 1986;314:1435-45. of pri8. Pietra GG, Edwards WD, Kay M, et al. Histopathology marypulmonaryhypertension. Circulation1989;80:1198-1206. 9. Wagenvoort. CA, Wagenvoort N, Takahashi T. Pulmonary venoocclusive disease. Involvement of pulmonary arteries and review of the literature. Hum Path01 1985;16:1033-41.
