Fenfluramine

A 36-year-old woman (height, 157 cm; weight, 117 kg; body mass index, 47.5) received fenfluramine and phentermine (fen-phen) for 7 months, and pulmonary hypertension subsequently developed. Her pulmonary arterial pressure was 56 mm Hg, and echocardiography showed right ventricular dilatation and hypokinesia. Cardiopulmonary arrest developed during right-heart catheterization, and she died 3 days later. At autopsy, right ventricular dilatation with fibroproliferative tricuspid valve was identified. The pulmonary arteries, including the main arteries and elastic arteries to the arterioles, revealed fibroproliferative plaque; the latter was more severe and more prominent in the upper lobes than in the lower lobes. Combined cardiac valvular disease and pulmonary hypertension appear to occur frequently in patients receiving fen-phen, and more autopsy cases of patients with a history of fen-phen usage are warranted to document the frequency of combined cardiac valvular disease and pulmonary hypertension in the United States.

Key words: cardiac valvular disease; fenfluramine; phentermine; pulmonary hypertension

Abbreviations: fen-phen = fenfluramine and phentermine; PPH = primary pulmonary hypertension

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Primary pulmonary hypertension (PPH) is rare, occurring in about two patients per 1 million population. (1) The incidence increases 30-fold in obese female patients who have received fenfluramine and phentermine (fen-phen) for > 3 months. (1,2) Fen-phen usage has attracted public attention in the United States, as it causes cardiac valvular lesions involving both the right-sided and left-sided cardiac valves, (3,4) We report the heart and lung autopsy findings in a documented case of PPH in a 36-year-old woman who received fen-phen for 7 months.

CASE REPORT

A 36-year-old woman (height, 157 cm; weight, 117 kg; body mass index, 47.5) was transferred from the outpatient cardiac laboratory to the ICU of University of Kansas Medical Center after cardiorespiratory arrest that occurred during right-heart catheterization. She had delivered a son by cesarean section in 1993 and received a diagnosis of gestational diabetes at that time. She had a history of fen-phen usage (daily dosage: fenfluramine, 30 mg; phentermine, 15 mg) for 7 months from February to August 1997. In February 1998, shortness of breath and easy fatigability developed. In June 1998, right-heart catheterization was performed; mean resting pulmonary artery pressure was 56 mm Hg (> 25 mm Hg is defined as pulmonary hypertension) with systolic and diastolic pressures of 98 mm Hg and 36 mm Hg, respectively. An echocardiogram showed right ventricular dilatation and hypokinesia as well as severe tricuspid insufficiency and moderate pulmonary insufficiency. In December 1998, she was placed on the lung transplantation list because of her severe pulmonary hypertension. On her last hospital admission in December 1999, cardiopulmonary arrest developed during right-heart catheterization. She was supported hemodynamically but required high volumes of oxygen with increasing amounts of pressure. After one round of cardiopulmonary resuscitation, she died on the third hospital day.

At autopsy, the heart weighed 400 g, as the right ventricle was markedly dilated and hypertrophic, with approximately three times more volume than that of the left ventricle. The right ventricular wall measured 1 cm in thickness. The circumferences of the tricuspid, pulmonary, mitral, and aortic valves were 13, 7, 9, and 5 cm, respectively. The dilated tricuspid valve revealed white, diffuse thickening of leaflets and cordae. Microscopically, the right ventricle showed multiple subendocardial plaques. The tricuspid valve was thickened with fibroproliferative lesions, mostly in the middle of leaflets (Fig 1). Less fibroproliferative lesion was noted in the pulmonary valve, and lesser fibroproliferative lesions were noted in the mitral and aortic valves. Both the right and left lungs were heavy, weighing 650 g and 670 g, respectively, with diffuse edema, congestion, and hemorrhage. Both pulmonary arteries were dilated to 5 cm in circumference, and there were numerous yellowish atheromatous plaques especially at the bifurcations of the arteries. On cut sections of the lungs, dilated and thickened cross sections of the arteries with yellowish atheromatous plaques were noted, more in the upper lobes than in the lower lobes (Fig 2). The pulmonary arteries were dissected, cross-sectioned, and embedded in one cassette by orientating each cross section. Histology of the thickened elastic arteries revealed diffuse and segmental thickening of intima and elastic media with > 80% occlusion in the continuous sections (Fig 3). Muscular arteries were diffusely thickened, and the arterioles revealed grade 1 to 4 lesions, (5,6) with complete occlusion by plexiform endothelial hyperplasia and organizing thrombi in 1 of 5 cross sections from the upper lobe and 1 of 10 cross sections from the lower lobe specimens (Fig 4). Both the thoracic and abdominal aorta revealed no atheromatous plaques.

[FIGURES 1-4 OMITTED]

DISCUSSION

PPH is a lethal disease with an estimated median survival of 2.5 years. (7) PPH occurs more frequently in female than in male patients, and PPH associated with fen-phen usage appears to occur almost exclusively in obese, middle-age women (mean [+ or -] SD age, 44 [+ or -] 8 years; body mass index > 30), as seen in this case. (1,4)

All 24 patients reported from the Mayo Clinic with cardiac valvular disease were female, 8 of whom also had PPH. (4) Thus, fen-phen usage causes both cardiac valvular lesions and PPH exclusively in female patients. PPH associated with fenfluramine usage from Europe corresponded to 20% of all reported PPH cases, and all of the fenfluramine-associated PPH occurred in female patients who had previously delivered babies. (1,4,7) The current patient initially received a diagnosis of PPH; however, autopsy findings disclosed both PPH and cardiac valvular disease.

Despite the fact that the numerous PPH cases associated with fenfluramine usage were reported from Europe, (1,8-10) the complete autopsy reports were relatively limited in the United States. The current study showed fibroproliferative lesions in the intima in all segments of the pulmonary arteries, including the main pulmonary arteries, and elastic, muscular, and small arteries. Severe lesions in the intrapulmonary arteries were more in the central upper lobes than in the central lower lobes. Plexiform arteriopathy is the most distinctive histopathologic finding in patients with PPH, being identified in 60% of all PPH cases. (11,12) As seen in this current case, plexiform arteriopathy is only found in 1 of every 5 to 10 tissue blocks of the lungs. (11) Fibroproliferative lesions were also noted in the tricuspid valve, with less involvement in the other three valves. The prevalence of any valvular disease was estimated to be 33% in those who have received fenfluramine or a combination of fen-phen. (3) As reported in one third of Mayo Clinic cases, combined cardiac valvular disease and PPH appear more common than previously anticipated. (4) At present, the etiology of PPH associated with fen-phen usage is unknown; however, the most likely pathogenesis of fen-phen-associated valvular lesions appears to be serotonin induced, and it is very similar to valvular lesions seen in carcinoid syndrome, (10,12,13) This hyperserotonemia may cause both valvular lesions and PPH by directly affecting the cardiac valves and pulmonary arteries. As noted in this case, cardiac valvular lesions were involved all four valves, with the tricuspid valve being most severely involved probably as a result of PPH, corresponding to the 40% of frequency in the tricuspid regurgitation observed in patients with PPH. (14) In future autopsy cases, all four cardiac valves should be examined microscopically, even though they may appear grossly normal. Accumulated autopsy studies on the patients with a known history of fen-phen usage should eventually clarify the relationship between the cardiac valvular disease and PPH.

REFERENCES

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(12) Strother J, Fedullo P, Masliath 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

(13) Robiolio PA, Rigolin VH, Wilson JS, et al. Carcinoid heart disease: correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization. Circulation 1995; 92:790-795

(14) Herve P, Launay JM, Scrobohari ML, et al. Increased plasma serotonin in primary pulmonary hypertension. Am J Med 1995; 99:249-254

* From the Department of Pathology, University of Kansas Medical Center, Kansas City, KS.

Manuscript received February 16, 2001; revision accepted July 11, 2001.

Correspondence to: Tatsuo Tomita, MD, Department of Pathology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160; e-mail: ttomita@kumc.edu

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