* Anorectic agents, such as aminorex and fenfluramine derivatives, have been associated previously with the development of primary pulmonary hypertension. The combination diet drug phentermine-fenfluramine (or "phen-fen") was recently marketed in the United States. We describe a case of a 39-year-old woman with rapidly progressing, fatal pulmonary hypertension following administration of phentermine-fenfluramine. Autopsy was remarkable for complex pulmonary vascular lesions most consistent with thrombotic arteriopathy.
(Arch Pathol Lab Med. 1999;123:539-540)
In the late 1960s and early 1970s, reports of a 20-fold increase in the incidence of pulmonary hypertension emerged from Switzerland, Austria, and Germany. These reports were associated with the introduction of a new diet drug, aminorex fumarate, to the European market in 1965.1 After its withdrawal from the market, the incidence of pulmonary hypertension decreased, but associations between pulmonary hypertension and other distantly related medications, such as phenformin, persisted.2 Use of the anorectic agent fenfluramine has since been reported in patients presenting with both reversible34 and irreversible56 pulmonary hypertension. Results of a European multicenter case-control study published in 1996 found that the use of anorectic agents increased the risk of pulmonary hypertension.7 The risk increased with the duration of exposure longer than 3 months and with a lead time of 1 year. We describe a case of rapidly progressing, fatal pulmonary hypertension in a patient with phentermine-fenfluramine ("phen-fen") use for 7 months. The complex pulmonary vascular lesions found at autopsy are most consistent with features of thrombotic arteriopathy.
REPORT OF A CASE
A 39-year-old woman was referred to our institution for evaluation of suspected primary pulmonary hypertension. Her medical history was significant for non-insulin-dependent diabetes mellitus, hypothyroidism, and left ankle fracture in May 1996.
The patient had no obstetrical history and no known history of alcohol or other drug abuse. In addition, her family history was negative for pulmonary disease or thromboembolic disorders. Phentermine-fenfluramine therapy was initiated in May 1996 for weight reduction (phentermine, 30 mg daily, and fenfluramine, 20 mg 3 times a day). Pretreatment weight was 65 kg at a height of 153 cm. In November, the patient developed exertional dyspnea with near syncope. She was diagnosed as having bronchitis during an emergency department visit, but her condition failed to improve on antibiotics. The patient sought further medical attention for persistent symptoms, and prednisone and methylprednisone were prescribed with little effect. In December, when symptoms persisted, pulmonary hypertension was suspected, and phentermine-fenfluramine use was discontinued. The maximum reported weight loss was 9 kg. By January, however, her dyspnea worsened. A ventilation-perfusion scan and lower extremity Doppler studies performed at that time were both negative, and her electrocardiogram showed no significant changes. Her medications included furosemide, albuterol, levothyroxine, metformin, and clonazepam.
On evaluation, pulmonary function tests were performed, which showed normal flow rates. An echocardiogram demonstrated normal left ventricular size and function, a small pericardial effusion, right atrial and ventricular enlargement, right ventricular hypertrophy, and severe tricuspid regurgitation. The patient was admitted to the hospital for right heart catheterization and nitric oxide trial. A lower extremity Doppler examination was performed, and no evidence of deep venous thromboses was seen. Right heart catheterization revealed mean right atrial pressure of 28 mm Hg, right ventricular pressure of 70/25 mm Hg, pulmonary artery pressure of 95/45 mm Hg (mean, 68 mm Hg), mean pulmonary capillary wedge pressure of 10 mm Hg, and cardiac output of 2.19 L/min. The patient was stable immediately following the catheterization, and nitric oxide was applied by nasal cannula. She was transferred to the medical intensive care unit thereafter where she received oxygen and an infusion of prostacyclin. She began to complain of chest pain an hour later. Over the next 5 hours she rapidly decompensated with falling blood pressure, continued chest pain with evidence of ischemia on electrocardiography, and bradycardia. Asystole ensued, and despite aggressive resuscitation the patient died that afternoon.
Autopsy revealed pulmonary vascular lesions affecting varying-sized arteries. Sections of the lungs showed intimal proliferations predominantly within small muscular pulmonary arteries and arterioles. These vessels also showed recanalization channels or organizing thrombi of various ages (Figure, A and B). Other lesions included eccentric intimal fibrosis, intimal proliferations containing myxoid matrix within large vessels (Figure, C and D), and focal organizing thrombi within larger musculoelastic arteries. Multiple sections stained with elastic-van Gieson failed to demonstrate definitive disruption of the vessel walls or extraluminal protrusion of the observed intimal proliferations as would be seen in classic plexiform lesions. Other typical features of plexogenic arteriopathy, such as dilatation lesions or necrotizing arteritis, were not evident. No postcapillary obstruction was evident, and no significant underlying pulmonary pathology was identified. Autopsy also showed moderate enlargement of the right heart representing dilatation with no grossly appreciable hypertrophy of the ventricular wall. However, the thickness of the right ventricular papillary muscles was mildly increased, and microscopic sections of the right and left ventricles showed scattered myocyte hypertrophy. Bilateral pleural effusions, pulmonary congestion and edema, and chronic passive congestion of the liver were associated findings. Atherosclerotic heart disease was a contributing factor to the patient's death. The left anterior descending coronary artery showed severe atherosclerosis with up to 80% occlusion of the lumen. Although the patient clinically showed electrocardiographic changes of ischemia and although significant single-vessel coronary atherosclerosis was found at autopsy, no anatomic evidence of myocardial infarction was demonstrated. This negative finding may be attributed to a hyperacute ischemic event. The heart valves showed no significant gross or microscopic abnormalities.
Pulmonary hypertension may occur in patients with no identifiable cause (ie, idiopathic or primary) or with certain systemic or cardiopulmonary diseases, such as congenital left-to-right cardiac shunts and chronic obstructive or fibrotic lung diseases. Although the underlying pathophysiology in most of these secondary pulmonary hypertension can be explained hemodynamically, the pathogenetic mechanism is still poorly understood in some conditions, including liver cirrhosis, toxic oil syndrome, human immunodeficiency virus infection, and diet-drug use, as in our patient, despite their apparent association with pulmonary hypertension. These cases have been reported to show unexplained pulmonary arteriopathy with plexiform lesions or thromboembolic indistinguishable from the microscopic findings in idiopathic or primary pulmonary hypertension?
We describe herein a case of fatal pulmonary hypertension that developed after administration of the combination diet drug phentermine-fenfluramine. Histopathologic appearance of the pulmonary vascular lesions in this case was most consistent with thrombotic arteriopathy, raising the question of whether these lesions were associated with phentermine-fenfluramine use or might be unrelated. A recent case of phentermine-fenfluramine-related pulmonary hypertension has been reported to show plexogenic arteriopathy.9 However, morphologic changes of plexogenic or thromboembolic arteriopathy have also been documented in more distant cases of aminorex-related pulmonary hypertension.1,10 Some of the pulmonary vascular lesions in our case showed glomeruloid or angiomatoid structures with questionable dilatation of small elastic arteries, findings possibly reminiscent of plexogenic arteriopathy. However, there was no demonstrable protrusion of the endothelial proliferative lesions through the vessel wall, and most proliferative lesions were confined within the lumina of variably sized arteries and arterioles. We favored a diagnosis of thrombotic arteriopathy for these findings according to criteria proposed in a report by the Primary Pulmonary Hypertension Registry,11 but precise classification of the histopathology was difficult because of some overlapping features. In this regard, while plexogenic arteriopathy is characterized by the presence of medial hypertrophy, eccentric or concentric laminar proliferation, and plexiform lesions, the thromboembolic lesions might display medial hypertrophy but no plexiform lesions.11 Some cases of thrombotic arteriopathy and plexiform arteriopathy may be pathogenetically related and also may show hybrid morphologic characteristics, as in this case. The cardiac valve leaflets showed none of the pathologic changes previously documented with exposure to this anorexiant.12 Together, the pathologic findings underscore the risk-benefit issues of phentermine-fenfluramine use and raise interesting questions regarding the pathogenesis and progression of primary pulmonary hypertension.
We thank William D. Edwards, MD, Mayo Clinic, Rochester, Minn, for his opinion on the case described.
1. Gurtner HP. Aminorex pulmonary hypertension. In: Fishman AP, ed. The Pulmonary Circulation. Philadelphia: University of Pennsylvania Press; 1990: 397-411.
2. Fahlen M, Bergman H, Helder G, Ryden L, Wallentin I, Zettergren L. Phenformin and pulmonary hypertension. Br Heart J. 1973;35:824-828.
3. Pouwels HMM, Smeets JLRM, Cheriex EC, Wouters EFM. Pulmonary hypertension and fenfluramine. Eur Respir/. 1990;3:606-607. 4. Douglas JO, Munro IF, Kitchin Al, Muir AL, Proudfoot AT. Pulmonary hypertension and fenfluramine. BMJ. 1981;283:881-883.
5. McMurray J, Bloomfield P, Miller HC. Irreversible pulmonary hypertension after treatment with fenfluramine. BMJ. 1986;292:239-240. 6. Atanassoff PG, Weiss BM, Schmid ER, Tornic M. Pulmonary hypertension and dexfenfluramine [letter]. Lancet. 1992;339:436.
7. Abenhaim L, Moride Y, Brenot F, et al, for the International Primary Pulmonary Hypertension Study Group. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med. 1996;335:609-616. 8. Kay JM. Vascular disease. In: Thurlbeck WM, Churg AM, eds. Pathology of the Lung. 2nd ed. New York, NY: Thieme Medical Publishers; 1995:932-995. 9. Mark EJ, Fatalas ED, Chang HT, Evans RJ, Kessler SC. Fatal pulmonary hypertension associated with short-term use of fenfluramine and phentermine. N Engl I Med. 1997;337:602-606.
10. Gurtner HP. Aminorex and pulmonary hypertension: a review. Cor Vasa. 1985;27:160-171.
11. Pietra GO, Edwards WD, Kay IM, et al. Histopathology of primary pulmonary hypertension. Circulation.1989;80:1198-1206.
12. Connolly HM, Crary JL, McGoon MD, et al. Valvular heart disease associated with fenfluramine-phentermine. N Engl Med. 1997;337:581-588.
Jennifer Strother, MD; Peter Fedullo, MD; Eunhee S. Yi, MD; Eliezer Masliah, MD
Accepted for publication December 14, 1998.
From the Departments of Pathology (Drs Strother, Yi, and Masliah) and Neurosciences (Dr Masliah), University of California, San Diego, La Jolla, Calif, and Pulmonary/Critical Care Division, Department of Medicine, University of California San Diego Medical Center, San Diego, Calif (Dr Fedullo).
Reprints: Eliezer Masliah, MD, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624.
Copyright College of American Pathologists Jun 1999
Provided by ProQuest Information and Learning Company. All rights Reserved