(Chest. 2002;121:649-652.)
© 2002
American College of Chest Physicians
Autopsy Findings of Heart and Lungs in a Patient With Primary Pulmonary Hypertension Associated With Use of Fenfluramine and Phentermine*
Tatsuo Tomita, MD and
Qiong Zhao, MD
*
From the Department of Pathology, University of Kansas Medical Center, Kansas City, KS.
Correspondence to: Tatsuo Tomita, MD, Department of Pathology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160; e-mail: ttomita{at}kumc.edu
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Abstract
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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
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Introduction
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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.
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Case Report
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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.
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Figure 1.. The tricuspid valve reveals intact architecture
with thickened fibroproliferative tissue, some of which forms
irregularly bulging plaques (P) [hematoxylin-eosin,
original x 150].
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Figure 2.. Lungs, gross. The dilated and thickened cross
sections of pulmonary arteries with yellowish fibroproliferative
plaques are mostly located in the central portions of the upper
lobes.
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Figure 3.. Cross sections of a dissected small pulmonary
artery. Hematoxylin-eosin (left column) and van
Gieson’s staining (right column) [all
original x 60] reveal both segmental and diffuse intimal thickening
and thickened elastic media. Top left, top
right: irregularly thickened elastic media.
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Figure 4.. Small and terminal artery. A small tangentially
cut muscular artery reveals diffuse thickening with fibrin thrombus
(f), and the cross sections of arterioles reveal plexiform endothelial
hyperplasia (1, 2, and 3) [hematoxylin-eosin,
original x 150].
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Discussion
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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 ± SD age,
44 ± 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
9
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.
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Footnotes
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Abbreviations: fen-phen = fenfluramine and phentermine;
PPH = primary pulmonary hypertension
Received for publication February 16, 2001.
Accepted for publication July 11, 2001.
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References
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-
Abenheim, L, Moride, Y, Bremost, F, et al (1996) Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 335,609-616[Abstract/Free Full Text]
-
Connolly, HM, McGoon, MD (1999) Obesity drugs and the heart. Curr Probl Cardiol 24,745-792[CrossRef][Medline]
-
Poston, WS, Foreyt, JP (2000) Scientific and legal issues in fenfluramine/dexfenfluramine litigation. Tex Med 96,48-56
-
Conolly, HM, Crary, J, McGoon, MD (1997) Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 337,581-588[Abstract/Free Full Text]
-
Katzenstein, AL, Askin, F (1990) Pulmonary hypertension and other vascular disorders. Surgical pathology of non-neoplastic lung disease 2nd ed. ,432-467 W.B. Saunders Philadelphia, PA.
-
Wilson, L, Tomita, T, Breniecke, M (1991) Fatal pulmonary hypertension in identical twins with systemic lupus erythematosus. Hum Pathol 22,295-297[CrossRef][ISI][Medline]
-
Dantzker, DR (1994) Primary pulmonary hypertension: the American experience. Chest 5,26S-28S
-
Brenot, F, Jerue, P, Petipretz, P, et al (1993) Primary pulmonary hypertension and fenfluramine use. Br Heart J 70,537-541[Abstract/Free Full Text]
-
Oakley, CW (1994) Primary pulmonary hypertension: case series from the United Kingdom. Chest 105,29S-32S
-
Brenot, F (1994) Primary pulmonary hypertension: case series from France. Chest 105,33S-41S
-
Mark, EJ, Patalas, ED, Chang, HT (1997) Fatal pulmonary hypertension associated with short-time use of fenfluramine and phentermine. N Engl J Med 337,602-606[Free Full Text]
-
Strother, J, Fedullo, P, Masliath, E (1999) Complex vascular lesions at autopsy in a patient with phentermine-fenfluramine use and rapidly progressing pulmonary hypertension. Arch Pathol Lab Med 123,539-540[Medline]
-
Robiolio, PA, Rigolin, VH, Wilson, JS, et al (1995) Carcinoid heart disease: correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization. Circulation 92,790-795[Abstract/Free Full Text]
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Herve, P, Launay, JM, Scrobohari, ML, et al (1995) Increased plasma serotonin in primary pulmonary hypertension. Am J Med 99,249-254[CrossRef][ISI][Medline]
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Abstract
Introduction
