Phentermine

* Context.-Few published studies of the pathology of fenfluramine-phentermine (fen-phen) valvulopathy, described by Connolly and colleagues in 1997, have appeared.

Objectives.-To define temporal changes in the morphology of the stuck-on plaques and to determine whether the plaques progress or regress after cessation of fen-phen.

Methods.-The available clinical information and pathology material from 35 aortic valves (AVs) and 43 mitral valves (MVs) from 64 patients were reviewed.

Results.-The valves fell into 3 groups: 17 AVs and 28 MVs had fen-phen lesions only, 2 AVs and 7 MVs had fenphen changes associated with other valve diseases, and 16 AVs and 8 MVs had no fen-phen changes. Fenfluraminephentermine-attributable dysfunction was regurgitation in all instances. Typical plaques showed proliferation of myofibroblastic cells with myxoid stroma. Small vascular channels and slight lymphocytic accumulations were often present. Deeper parts of some plaques had dense fibroelastic tissue underlying typical plaque.

Conclusions.-Considerable individual variation in the time course of anorectic agent use and the severity of fenphen valvulopathy was observed. Possible plaque regression could not be assessed from this study. The observations suggest that in some patients fen-phen-induced plaques may continue to have surface proliferation despite drug withdrawal.

(Arch Pathol Lab Med. 2001;125:1555-1561)

In 1997, Connolly et all published a landmark study of valvular disease in patients who had taken the anorectic drug combination fenfluramine-phentermine (fenphen). The report contained 24 cases, and histopathology was described for 3. Each valve had "stuck-on" plaques comprised of myofibroblasts in a myxoid matrix. These lesions encased the leaflets and chordal structures, while leaving the valve structure intact. This constellation of findings has since been referred to as fen-phen valvulopathy. Since then, much work has focused on determination of disease prevalence, dose effect, and long-term clinical effects, generally based on echocardiography. Few histologically based investigations have appeared. In fact, the medical literature contains a total of 9 cases and 11 valves (3 aortic valves [AVs], 8 mitral valves [MVs]) with histology of variable detail.1-4 Two published autopsy cases have focused on pulmonary hypertension, with minimal description of the valvular changes.5,6 Other case reports have suggested fen-phen lesions in a right ventricular biopsy7 and in a transplant heart that had been explanted from a fen-phen user.8 The goals of the current study were to more fully define the range and temporal course of histologic appearances of fen-phen valvulopathy and to highlight microscopic features that distinguish it from other valve diseases. In addition, an effort was made to assess the likelihood that lesions induced by anorectic agents could progress despite cessation of therapy.

MATERIALS AND METHODS

Material was obtained through consultation and from the surgical pathology and autopsy pathology files of The Johns Hopkins Hospital (Baltimore, Md). Cases were selected by 2 criteria: the availability of AV and/or MV pathology material, and documented exposure to anorectic agents, including fenfluraminephentermine in combination (fen-phen), fenfluramine alone, or dexfenfluramine alone. Sixty-four cases comprising a total of 78 valves (35 AVs, 43 MVs) that met these criteria were identified. Sixty cases and 72 valves (33 AVs, 39 MVs) were the result of surgical valve replacement, while the remaining 4 cases and 6 valves (2 AVs, 4 MVs) were obtained from autopsy material. Each valve was assessed on the bases of clinical features, gross appearance, and histology. For each case, sections stained with hematoxylin-eosin and either Verhoeff-van Gieson elastic stain or Movat pentachrome stain were examined. Sections from 16 cases (3 AVs, 15 MVs) were also stained with the immunohistochemical marker Ki-67, an indicator of cell proliferation. Available clinical data were reviewed, including notes from office visits, pharmacy records, surgical notes, echocardiogram reports, and surgical pathology reports.

Assessment of valvular disease was based on previously described gross and microscopic findings in AVs and MVs.1',9-11 The more important disease entities will be briefly described here (Figures 1-4). Fenfluramine-phentermine valvulopathy (Figures 1-3) shows gross thickening of the valve leaflets with chordal fusion. Histologically, the valve architecture is intact, with encasement of the leaflets and chordae tendineae by a stuck-on, plaquelike lesion made up of myofibroblasts in a myxoid extracellular matrix. Lymphocytic accumulation and small vascular channels have been inconsistently described.

The effects of fen-phen must be distinguished from other forms of valve disease. The free edges of the valves in conditions with chronic stenosis or regurgitation may have hemodynamically induced fibroblastic proliferation that is more lamellar and hypocellular than fen-phen lesions. The consequent "rolling" of the valve tip (Figure 4, A) is more a consequence of AV disease than a cause of it. This rolling lesion may also be seen in cases of AV disease caused by pathology in the aorta, such as aortic annular dilatation.

Rheumatic heart disease is characterized by gross commissural fusion, leaflet thickening, and fusion of chordae. The thickening consists of a more dense, lamellar, paucicellular fibrosis, which tends to extend down to the heads of the papillary muscles. Neovascularization and lymphocytic infiltrates may be prominent (Figure 4, B). Contrary to fen-phen valvulopathy, rheumatic heart disease consistently shows fibrosis of native valve substance.

Floppy MV, also known as myxomatous MV, is often detected clinically as MV prolapse. Grossly, the valves show thickening particularly at the lines of closure. The valves have an increased surface area, and the mitral annulus is dilated. So-called endocardial pulley lesions caused by stretching of chordae over the endocardial surface during ventricular contraction are common, and rupture of chordae may occur. Histology of floppy MV shows proliferation of loose myxoid matrix similar to that seen in fen-phen valves (Figure 4, C). However, the myxoid material is mainly within the substance of the valve. The result is a disrupted lamina fibrosa made up of small bundles of native collagen that are widely separated by myxoid tissue. Small surface plaques, similar to those seen in fen-phen lesions, may occur on the ventricular aspect of the leaflet. Lymphocytes and vascular channels are distinctly rare in floppy MV.

Calcific aortic stenosis is characterized by marked calcification (Figure 4, D). Congenital bicuspid AV and rheumatic aortic stenosis may also acquire similar calcific changes in the sinuses of Valsalva. Aortic rheumatic heart disease commonly shows commissural fusion.

RESULTS

The 64 patients included 54 (84%) women and 10 (16%) men. Fifty women and 10 men were surgical patients, while 4 women had been autopsied. The overall average age was 50.5 years (range 23-77 years). Both the AVs and MVs were involved in 14 (22%) cases. None of the patients had a history of carcinoid syndrome or ergotamine use.

The 78 valves fell into 3 categories, as summarized in the Table. Overall, 54 valves (69%) had evidence of fenphen changes, and 45 valves (58%) showed fen-phen valvulopathy only. Twenty-four valves (31%) showed no fenphen changes. Among the 43 MVs, 28 (65%) had fen-phen lesions only, 7 (16%) showed fen-phen changes in association with other valve diseases, and 8 (19%) had no fenphen changes. All MVs with fen-phen lesions had clinically evident regurgitation, while 4 valves also had a mild component of stenosis. In addition to the classic loose myxoid surface plaque usually noted in mitral fen-phen valvulopathy, some plaques had deeper regions that were more dense but hypocellular, and had an appearance of fibroelastic tissue (Figure 2). Small vascular channels and lymphocytic accumulations were often noted. Mitral disease seen in association with fen-phen lesions included 3 cases with floppy MV, 2 cases with rheumatic heart disease, 1 case with calcific mitral annulus fibrosus, and 1 with superimposed infectious endocarditis (Figure 5). Mitral disease lacking fen-phen changes included 4 valves with rheumatic heart disease, 2 with floppy MV, and 2 with unclear etiology. Relative to fen-phen valvulopathy, the rheumatic valves showed more lymphocytic infiltration and much larger, thick-walled neovascularization.

Among the 35 AVs, 17 (49%) showed fen-phen lesions only, 2 (5%) had fen-phen plaques superimposed on other valve disease, and 16 (46%) had no fen-phen changes. Aortic fen-phen valvulopathy was evident in 2 patterns (Figure 3). Some valves showed a thin flat surface plaque located on the ventricular surface of the leaflet and surrounding the free edge of the leaflet. Such plaques often appeared to compress or fold the leaflet edge. The other pattern of AV involvement showed a rounded distinct surface nodule in the middle of the valve. Unlike the affected MVs, lymphocytic accumulation and vascular channels were distinctly uncommon in the AVs. The aortic plaques were more myxoid and loose overall, and showed less of the dense fibroelastic areas noted in the MVs. All cases of aortic fen-phen valvulopathy showed clinical regurgitation. Other AV diseases seen in association with fen-phen were calcific aortic stenosis in one case and idiopathic aortic dilatation with aortic regurgitation in another. Aortic valves lacking fen-phen changes included 9 with calcific aortic stenosis, 2 with bicuspid AV, and the remaining 5 were due to either aortic pathology or were of unclear etiology.

Duration of drug exposure was known in 52 cases (comprising 62 valves), with a mean of 11.1 months overall (range 248 months). Patients with fen-phen affecting the AV averaged 54.1 years of age, versus 50.3 years in the MV group. Aortic fen-phen valvulopathy was associated with an average duration of drug exposure of 11.1 months (range 4-30 months) and showed a period between drug cessation and surgery of 17.7 months (range 2 weeks to 35 months). Mitral fen-phen valvulopathy was associated with a somewhat shorter duration of drug exposure (10.1 months, range 2-24 months) and shorter interval from drug cessation to surgery (13.8 months, range 2 weeks to 36 months).

Immunohistochemical staining with the cell proliferation marker Ki-67 was performed on 16 surgical cases with fen-phen plaques (3 AVs, 15 MVs) (Figure 6). Twelve of the cases had only fen-phen changes, 2 had fen-phen changes superimposed on rheumatic heart disease, and 2 had a combination of fen-phen changes and floppy MV Twelve cases (3 AVs, 11 MVs) showed at least occasional Ki-67-positive nuclei within fen-phen plaques, while the other 4 cases (2 AVs, 2 MVs) showed no staining. The positively staining valves were associated with a shorter duration of drug exposure (10.9 vs 17.3 months) and a shorter interval from cessation of drug exposure to surgery (11.5 vs 16.3 months); however, the degree of staining was variable and the chronological range was wide for both groups.

COMMENT

The medical literature contains many studies of fenphen effects on cardiac valves from pharmacologic, echocardiographic, and epidemiologic perspectives. Far fewer publications concerning the histopathology of fen-phen have appeared. In the original report by Connolly and coworkers,1 3 cases had histology, with a total of 3 MVs and 1 AV. Grossly, the valves were described as white and glistening. Histologically, the MVs showed intact valve architecture with encasement of the leaflets and chordae tendineae by a plaquelike lesion. Changes in affected AVs were described as similar, but less extensive. The plaque was made up of apparent myofibroblasts in an abundant extracellular matrix of glycosaminoglycans and collagen. These stuck-on plaques were thought to be identical to those seen in carcinoid syndrome and ergotamine-induced valvular disease. Indeed, in 1956 McKusick16 reported a case of carcinoid heart disease involving the MV in a patient with an atrial septal defect. Histology showed fibroelastic proliferations on the valve surface that were strikingly similar to those seen in fen-phen valvulopathy (Figure 7). Only rare elastic fibers have been observed by electron microscopy in carcinoid plaques from the right side of the heart,17 suggesting that elastogenesis may be a function of different mechanical effects on plaques in the right and left sides of the heart. Two reports have noted gross commissural fusion in patients with ergotamine exposure,18,19 a finding distinctly unusual for fen-phen valve disease.

Steffee et al2 reported 3 cases of fen-phen valvulopathy (2 MVs, 1 AV) with extensive histologic evaluation and comparison to both postinflammatory valvular disease and a normal MV obtained at autopsy. Gross changes of the MV included irregular thickening with opaque white nodules and plaques, as well as fused chordae tendineae. The AV had a distinctly nodular plaque. Microscopically, the lesions consisted of a superficial fibromyxoid proliferation with a varied shape; some were flat, while others were dome-shaped. Most of the plaquelike lesions contained myofibroblast-like cells in a lightly basophilic extracellular matrix, while other areas were more fibrous and lightly eosinophilic. Special stains demonstrated a generally preserved elastic fiber layer, with some splaying at the base of plaques. A small amount of lymphocytic infiltrate was noted and identified as predominantly T cell in origin by immunohistochemical stains. Giemsa stain showed mast cells in some lesions. A tendency to involve the "downstream" surface of the valves was noted. Contrary to the postinflammatory cases, the fen-phen valves did not show neovascularization.

Biswas and colleagues3 described one patient who underwent a MV replacement 2 years after cessation of fenphen, which she had been exposed to for only 3 weeks. Focal thickening was noted on the MV Histology demonstrated fibroproliferative lesions that encased the chordae tendineae. The proliferation varied from cellular and myxoid to hypocellular with a dense fibroelastic extracellular matrix. Minimal neovascularization was noted, but no inflammation was present.

Prasad et al8 reported an interesting case of a woman with 8 months' fen-phen exposure who died suddenly. Her heart was harvested and used for transplant. At the time of harvest, 3 linear verrucous lesions were noted on the atrial surface of the mitral annulus. While the lesions had a stuck-on appearance similar to those seen with fenphen, there was no leaflet or chordal involvement. It was proposed that the lesions represented the earliest sites of anorexigen-induced valvulopathy, however the entire valve was not examined histologically, and the gross appearance given was not typical of fen-phen changes.

Two autopsy cases involving fen-phen have also appeared in the literature, although both focused on the patients' pulmonary hypertension, another known risk of anorectic agent use.20 One case5 had brief mention of valves absent of fen-phen changes. Another case did not mention the cardiac valves.6

The current study was undertaken as a large-scale assessment of the histopathology of fen-phen valvulopathy. Among patients with fen-phen lesions only, those undergoing AV replacement were slightly older and had a somewhat longer interval from drug cessation to surgery than those undergoing MV replacement. Patients with non-fenphen MV disease tended to be younger and had a shorter interval to surgery than other groups. The group lacking fen-phen lesions had several other valve diseases, including floppy MV, rheumatic heart disease, and calcific aortic stenosis. One case showed bacterial endocarditis superimposed on fen-phen changes, underscoring the importance of antimicrobial prophylaxis, as noted by others.21

With few exceptions, the fen-phen lesions seen in these cases had an appearance similar to previous descriptions. The MVs showed more evidence of lymphocytic accumulation and small, thin-walled vessels than usually noted. Both findings were much less common in the AVs. Like previous workers,2,3 we noted variation in the consistency of plaques; some areas were loose and myxoid, while others comprised dense, hypocellular, fibroelastic tissue.

Another goal of the study was to assess the degree of progression or regression of fen-phen lesions. There is some published evidence for regression of fen-phen valvulopathy, at least on grounds of echocardiographic studies and clinical symptomatology.22-24 We found that in a select group of cases, fen-phen plaques stained with Ki67, suggesting ongoing lesion proliferation. Experimental studies have shown an increase in serotonin 5-HT(2B) receptors in valve tissue exposed to fenfluramine and dexfenfluramine.25,26 Serotonin has a known mitogenic effect on various cells, including those of the cardiovascular system.27 It is possible that drug-induced myofibroblastic proliferation induced by fenfluramine may continue after drug withdrawal as a response to endogenous serotonin. Evidence has been presented showing a correlation between duration of drug exposure and the presence of echocardiographic valve abnormality,28 but not necessarily the severity of valvular defect. The current cases showed wide variation in the severity of fen-phen lesions and did not correlate with either the duration of drug exposure or the interval between drug cessation and surgery.

Some limitations of the current study merit brief mention. Aside from the 4 autopsy cases, all examined valves were obtained through surgery, thus the material is only from valvular disease severe enough to be symptomatic. Consequently, the study does not provide any evidence on the general prevalence of disease in the fen-phen-exposed population, nor does it allow us to draw conclusions about the appearance of lesions on valves not requiring surgery. Since the valves can be assessed histologically at only one point in time, progression or regression in individual cases cannot be fully evaluated by this study.

In summary, we present the first large-scale study on the histopathology of fen-phen valvulopathy. The cases examined here emphasized the marked individual variation in severity and location of valvular lesions induced by anorectic agents. No dose-response effect was found, since duration of exposure did not correlate well with the severity of lesions. Immunohistochemical studies of a cell proliferation marker suggested that in some cases the plaques might continue to enlarge, perhaps under the influence of endogenous serotonin, despite cessation of anorectic agent therapy. If confirmed, this finding would suggest a need for continuing observation of exposed individuals.

References

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2. Steffee CH, Singh HK, Chitwood WR. Histologic changes in three explanted native cardiac valves following use of fenfluramines. Cardiovasc Pathol. 1999;8: 245-253.

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16. McKusick VA. Carcinoid cardiovascular disease. Bull Johns Hopkins Hosp. 1956;98:13-36.

17. Himbert J, Even P, Grosgogeat Y, Letac B. Cardiopathie carcinoide (nouvelle observation clinique, hemodynamique, biologique et anatomique). Arch Mal Coeur. 1965;58:1638-1656.

18. Hauck AJ, Edwards WD, Danielson GK, Mullany CJ, Bresnahan DR. Mitral and aortic valve disease associated with ergotamine therapy for migraine. Arch Pathol Lab Med. 1990;114:62-64.

19. Hendrikx M, Van Dorpe J, Flameng W, Daenen W. Aortic and mitral valve disease induced by ergotamine therapy for migraine: a case report and review of the literature. J Heart Valve Dis. 1996;5:235-237.

20. Rich S, Rubin L, Walker AM, Schneeweiss S, Abenhaim L. Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension. Chest. 2000;117:870-874.

21. Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services Interim Public Health Recommendations, November 1997. MMWR Morb Mortal Wkly Rep. 1997;46: 1061-1066.

22. Cannistra LB, Cannistra Al. Regression of multivalvular regurgitation after the cessation of fenfluramine and phentermine treatment [letter]. N Engl J Med. 1998;339:771.

23. Cannistra LB, Davis SM, Bauman AG. Valvular heart disease associated with dexfenfluramine [letter]. N Engl IJ Med. 1997;337:636.

24. Hensrud DD, Connolly HM, Grogan M, Miller FA, Bailey KR, Jensen MD. Echocardiographic improvement over time after cessation of use of fenfluramine and phentermine. Mayo Clin Proc. 1999;74:1191-1197.

25. Fitzgerald LW, Burn TC, Brown BS, et al. Possible role of valvular serotonin

5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000;57:75-81.

26. Rothman RB, Baumann MH, Savage JE, et al. Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation. 2000;102:2836-2841.

27. Fanburg BL, Lee SL. A new role for an old molecule: serotonin as a mitogen. Am I Physiol. 1997;272(5 pt 1):L795-L806.

28. Jollis JG, Landolfo CK, Kisslo J, Constantine GD, Davis KD, Ryan T. Fenfluramine and phentermine and cardiovascular findings: effect of treatment duration on prevalence of valve abnormalities. Circulation. 2000;101:2071-2077.

Keith E. Volmar, MD; Grover M. Hutchins, MD

Accepted for publication August 1, 2001.

From the Department of Pathology, The Johns Hopkins Medical In

stitutions, Baltimore, Md.

Dr Hutchins has been a paid consultant, on an hourly basis, to attorneys representing either individual patients with exposure to weight loss preparations or the industries that manufacture such products.

Reprints: Keith E. Volmar, MD, Department of Pathology, The Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287 (e-mail: kvolmar@pds.path.jhu.edu).

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