Phentermine

To the Editor.-In the June 1999 issue of the ARCHIVES, Strother et all reported the case of a middle-aged woman who had ingested phentermine and fenfluramine for weight reduction during 8 months. The lesions of pulmonary muscular arteries shown in Figure 1, A and B, which the authors interpreted as focal organizing thrombi, are, in my opinion, plexiform lesions. The lesion in Figure 1, A, is intimal hyperplasia, and Figure 1, D, represents arterial necrosis. These lesions correspond to grades IV, II, and VI, respectively, in the grading system established by Heath and Edwards2 for the lesions of muscular arteries of 100 (mu) to 1000 (mu)m diameter in pulmonary hypertensive vascular disease or to pulmonary plexogenic arteriopathy as proposed by a World Health Organization Working Group.3 My opinion is established on the morphologic study of the lungs of 37 patients who died in Switzerland after having ingested aminorex fumarate (another weight-reducing pill) during the so-called aminorex epidemic reviewed by Gunners Pulmonary hypertensive vascular disease affected 582 patients in Austria, former West Germany, and Switzerland during a limited period: from 1965, when the drug was introduced, until 1968, when it was withdrawn from the market. None of our cases showed arterial thromboses.

In 2 cases of phentermine-related pulmonary hypertensive vascular disease submitted for assessment (unpublished data), I found similar vascular lesions. However, none of the patients (aminorex or phentermine cases) showed any correlation between the severity of the lesions and the drug intake (quantity or duration).

In the absence of any serious experimental model published, the mechanism by which the lesions related to anorexigens (aminorex, phentermine, or fenfluramine hydrochloride) remains unexplained. One can only hypothesize that in some people (about 0.2% in the aminorex cases), some factors did cause an increase in the tonus of muscular pulmonary arteries, which was followed by a vasospasm, resulting in an endothelial lesion on which fibrinoid material was deposited, producing intimal proliferation. The latter, rich in myointimal cells and smooth muscular cells, might have contributed to the aggravation of the pulmonary hypertension induced by the vasospasm.

I agree with the question Strother et al raised about the risk-benefit operation of the new anorexigens, which in turn leads to the more serious inquiry into unrecognized cases of pulmonary hypertensive disease in the countries where these drugs are marketed.

SVEN WIDGREN, MD

Institut Neuchatelois d'Anatomie Pathologique Les Cadolles CH-2002 NeuchAtel, Switzerland

1. Strother J, Fedullo P, Yi ES, Masliah E. Complex vascular lesions at autopsy in a patient with phentermine-fenfluramine use and rapidly progressing pulmonary hypertension. Arch Pathol Lab Med. 1999;123:539-540.

2. Heath D, Edwards JE. The pathology of hypertensive pulmonary vascular disease. Circulation. 1958;18:533-547.

3. Hatano S, Strasser T. L'Hypertension Pulmonaire Primitive: Rapport d'une Reunion de TOMS, Geneve, 15-17 Octobre 1973. Geneva, Switzerland: Organisation Mondiale de la Sante; 1975:146.

4. Widgren S. Pulmonary hypertension related to aminorex intake: histologic, ultrastructural, and morphometric studies of 37 cases in Switzerland. Curr Top Pathol. 1977;64:1-63.

5. Gunner HP. Aminorex and pulmonary hypertension: a review. Cor Vasa. 1985;27:160-171.

In reply.-We thank Dr Widgren for his interest in our case report and agree with his view on Figure 1, A and B, as plexiform lesions as an alternative interpretation. We admit that one may label these lesions even as "classic" plexiform lesions, whereas others may disagree and prefer to label them as thrombotic lesions. Therefore, we used the term complex vascular lesion in the title to avoid subjectivities and discrepancies in interpretation.

Morphologic changes in the pulmonary arteries of the patients with diet drug use-related pulmonary hypertension have been reported as plexogenic pulmonary arteriopathy similar to the changes in children with pulmonary hypertension and large congenital left-to-right shunts or primary pulmonary hypertension.1 There is considerable controversy regarding clinical and pathogenetic implication of various morphologic lesions in pulmonary hypertension, especially thrombotic and plexiform lesions in muscular pulmonary arteries.2 Differentiation of plexiform lesions and cellular organizing or recanalizing thrombi can be difficult despite their prognostic implication as reported by the National Primary Pulmonary Hypertension Study Group sponsored by the National Heart, Lung and Blood Institute.3 A previous morphologic study on familial primary pulmonary hypertension cases reported a marked heterogeneity of pathologic lesions within an individual and among the affected members of a family.2 This study also found frequent coexistence of thrombotic and plexiform lesions within and among families and concluded that these 2 lesions may simply represent different manifestations of the same process rather than a distinctly different biologic process.2 A morphologic study demonstrated the identical cellular immunohistochemical profile of cellular thrombi and plexiform lesions, which also supported such a conclusion.4

EUNHEE S. YI, MD

Department of Pathology

ELIEZER MASLIAH, MD

Departments of Pathology and Neurosciences University of California, San Diego La Jolla, CA 92093-0624

1. Gunner HP. Aminorex pulmonary hypertension. In: Fishman AP, ed. The Pulmonary Circulation. Philadelphia: University of Pennsylvania Press; 1990:397-411.

2. Loyd JE, Atkinson JB, Pietra GG, Virmani R, Newman JH. Heterogeneity of pathologic lesions in familial primary pulmonary hypertension. Am Rev Respir Dis. 1998;138:952-957.

3. Pietra GG, Edwards WD, Kay M, et al. Histopathology of primary hypertension: a qualitative and quantitative study of pulmonary vessels from 58 patients in the National Heart, Lung and Blood Institute, primary pulmonary hypertension registry. Circulation. 1989;80:1198-1206.

4. Ahn HK, Kim H, Strother J, et al. Cellular immunohistochemical profile is identical in thrombotic and plexiform lesions of pulmonary hypertension. Am J Respir Crit Care Med. 1999;159:A1 57.

Copyright College of American Pathologists Jun 2000
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