Pulmonary Hypertension, Hyperthyroidism, and Fenfluramine: A Case Report and Review From Medscape G

1
 Pulmonary Hypertension, Hyperthyroidism, and
Fenfluramine A Case Report and Review From
Medscape General MedicinePosted
11/08/2006 Leung Ying Ying, MBChB, FHKAM Tang
Kam Shing, MBBS, FHKAM Tsang Chiu Chi, MBBS,
FHKAM Chan Chi Kin, FRCP, FHKAM Wong Kwan
Keung, FRCP, FHKAM Yu Alex Wai-yin, FRCP, FACP,
MD

• 96-5-18 ????
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Case Report

• A 53-year-old woman was admitted to the intensive
  care unit on June 21, 2005 for sudden cardiac
  arrest.
• She had a history of hyperthyroidism (5 years
  prior) and did not pursue follow-up.
• According to her family, she had a 2-week history
  of exertional shortness of breath.
• On day of admission, she developed a sudden
  increase in dyspnea at home and collapsed shortly
  afterwards.

3
Case Report

• She was not known to be taking long-term
  medications, but had been short-tempered and had
  significant weight loss over the past 1-2 years.
• On physical examination, patient was not obese.
• There was no goiter, and there were no signs of
  connective tissue diseases or deep vein
  thrombosis.
• Chest examination was normal.
• Heart examination revealed a mitral regurgitation
  murmur.
• Chest radiography showed cardiomegaly and mild
  congestion.

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Case Report

• Brain computer tomography revealed cerebral edema
  that is compatible with hypoxic brain damage.
• Electrocardiogram post resuscitation showed sinus
  rhythm without ischemic change. Creatinine kinase
  was only slightly elevated to 387 IU/L (normal
  range, 48-197 IU/L).
• Serum antinuclear antibody titer was 180.
• Blood tests were compatible with hyperthyroidism
  with thyroid stimulating hormone (TSH) and free
  thyroxine (fT4), 0.27-4.20mI/L) and 30.4 pmol/L (normal range,
  12.0 - 22.0 pmol/L), respectively.

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Case Report

• Two hours after successful resuscitation, the
  patient had persistent hypertension and
  tachycardia, with blood pressure and pulse rate
  of 220/100 mm Hg and 100 beats per minute,
  respectively.
• She was treated with propylthiouracil, Lugol's
  iodine solution, and hydrocortisone.
• She remained unconscious.

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Case Report

• Five hours later, she suffered hemodynamic
  deterioration requiring inotrope support.
• Echocardiography revealed an ejection fraction of
  87 without regional wall abnormality, a
  predominance of right heart failure, and moderate
  aortic regurgitation (AR) and mitral
  regurgitation (MR), without leaflet thickening
  and right ventricular dilatation.
• Significant PAH (pulmonary artery hypertension)
  was confirmed, with the pulmonary arterial
  systolic pressure (PASP) grossly elevated to 70
  mm Hg.
• Her condition deteriorated rapidly, and she
  succumbed 5 days later.

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Case Report

• Subsequently, the patient's family found bottles
  of weight-loss pills from her room, which tested
  positive for fenfluramine.
• Fenfluramine derivatives were also detected in
  the patient's first urine sample.
• Serum thyroglobulin was 21mcg/L, which is
  inappropriately low, suggesting an exogenous
  source of thyroxine leading to hyperthyroidism.

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Case Report

• Autopsy confirmed right ventricular hypertrophy
  and fibromyxoid change on mitral and aortic
  valves.
• The pulmonary arteries revealed
  fibroproliferative plaques.

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Discussion-PAH

• PAH is a rare and often fatal disease.
• It tends to occur in women in their third or
  fourth decades.
• The factors leading to its development are still
  unknown.
• Current concepts envisage individual
  susceptibility with some triggering stimulus,
  leading to an imbalance of vasoactive mediators.

10
Discussion

• Patients with PAH have an excess of
  vasoconstrictive mediators such as endothelin-1,
  thromboxane, and serotonin in the pulmonary
  vascular bed, and the production of vasodilators
  such as prostacyclin and nitric oxide is
  impaired.
• These abnormalities promote downstream
  inflammation, activation of cytokines, and
  vascular remodeling.
• The end result is vasoconstriction, followed by
  vascular intimal proliferation and fibrosis, in
  situ thrombosis, and plexigenic arteriopathy.

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Marc Humbert et al 2004 NEJM p1425
12
Discussion

• PAH is defined as
• a mean PASP 25 mm Hg at rest or 30 mm Hg
  during exercise.
• The Doppler echocardiography definition of PAH is
  based on tricuspid regurgitation jet 2.8
  m/sec.2
• PAH is classified as primary or secondary
  according to World Health Organization (WHO)
  criteria.

13
Marc Humbert et al 2004 NEJM p1425
14
2003 Lancet, Runo J.R. p1533
15
Discussionsympathomimetics and PAH

• Fenfluramine derivatives, including fenfluramine
  and dexfenfluramine, are sympathomimetics.
• They exert an anorexic action by activating the
  serotonin pathway in the brain.
• Serotonin is itself a potent vasoconstrictor and
  can induce platelet aggregation.
• It also interacts with 5-hydroxytryptamine (5-HT)
  receptors and promotes pulmonary vascular smooth
  muscle proliferation.3

16
Farber H.W. et al 2004 NEJM P1655
17
Discussion

• The mechanism responsible for the development of
  PAH in patients exposed to fenfluramine is
  unclear.
• Weir and colleagues4 demonstrated that, in a
  rat model, apart from the vasoconstrictive effect
  of serotonin, fenfluramine causes PAH by
  inhibiting potassium channels in the pulmonary
  artery smooth muscle cells. This leads to
  vasoconstriction, followed by progressive
  vascular growth and remodeling.
• Only a minority of patients exposed to
  fenfluramine derivatives develop PAH, suggesting
  a genetic susceptibility in a subset population.

18
Adrogué H.J. and Madias N.E. NEJM
2007(356)1966-1978,
19
Adrogué H.J. and Madias N.E. NEJM
2007(356)1966-1978,
20
Adrogué H.J. and Madias N.E. NEJM
2007(356)1966-1978,
21
Adrogué H.J. and Madias N.E. NEJM
2007(356)1966-1978,
22
Farber H.W. et al 2004 NEJM P1655
23
Discussion

• In the early 1990s, a cluster of cases of PAH was
  reported among patients who had used derivatives
  of fenfluramine.5
• Subsequent study confirmed a causal relationship
  between fenfluramine with PAH and valvular heart
  disease (VHD), leading to its withdrawal from the
  global market in 1997.6
• In a multicenter case-controlled study in Europe,
  the use of any appetite suppressant within the
  previous year was associated with a 10-fold
  increase in the development of PAH.7
• The risk further increased to 20-fold with
  usage of the drug for more than 3 months.
• The majority of patients had used fenfluramine
  and dexfenfluramine in that study.

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Discussion

• In another study,8 the median survival of 194
  patients diagnosed with primary PAH between 1981
  and 1985 was only 2.5 years, according to the
  Patient Registry for the Characterization of
  Primary Pulmonary Hypertension supported by the
  National Heart, Lung, and Blood Institute.
• In the study by Simmoneau and colleagues, the
  overall survival of fenfluramine-induced PAH was
  as poor as that of primary PAH.3

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Discussion sympathomimetics and VHD

• The most commonly reported valvulopathy among
  patients exposed to fenfluramine are AR and MR,
  and the risk correlated to the duration of
  exposure.
• The relative risk ratios of AR and MR were 2.32
  (95 confidence intervals 1.79 to 3.01, P .00001) and 1.55 (95 confidence intervals 1.06
  to 2.25, P .02), respectively, in a
  meta-analysis involving 1279 patients exposed to
  fenfluramine.9

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Discussion

• Fenfluramine valvulopathy is characterized by
  fibroplasia and plaque-like encasement of intact
  valve leaflets and chordal structures.
• This is identical to the histopathologic features
  in malignant carcinoid syndrome and
  ergotamine-induced valve disease.
• The mechanism of valve injury has not been
  determined but is believed to be serotonin
  mediated.6,10,11

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Figure 3. Carcinoid Heart Disease. The pulmonary
valve is thickened and fibrotic.
Photograph courtesy of James R. Stone, M.D.,
Ph.D., Department of Pathology, Brigham and
Womens Hospital, Boston.
KULKE M.H. 1999 NEJM, p858
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Figure 3. Photomicrographs of Resected Mitral
Valve from Patient 2. In Panel A, a low-power
view (elasticvan Gieson stain, 36) shows intact
valve architecture with stuck-on plaques
(arrows). In Panel B, a high-power view
(hematoxylin and eosin, 360) shows proliferative
myofibroblasts in an abundant extracellular matrix
Connolly H.M. 1997 NEJM, p581,
29
Bryan L. Roth, 2007 NEJM, p6-9
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DiscussionHyperthyroidism and CV system

• Hyperthyroidism affects the cardiovascular system
  in several ways.
• It plays a role in sinus tachycardia, atrial
  fibrillation, decreased exercise tolerance,
  dilated cardiomyopathy, and, in some cases,
  high-output congestive heart failure.
• PAH related to hyperthyroidism has been reported.
  
• Resolution of PAH after successful treatment of
  hyperthyroidism has also been demonstrated.

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Discussion Hyperthyroidism and PAH

• Several mechanisms have been suggested in the
  pathogenesis, including an autoimmune process
  leading to pulmonary endothelial damage or
  dysfunction increased cardiac output causing
  pulmonary endothelial injury and increased
  metabolism of intrinsic pulmonary vasodilating
  substances.12
• A transthoracic Doppler echocardiography study in
  a cohort of patients with Graves' disease
  reported mild PAH in 7 out of 17 patients.
• Correlations between TSH and PASP, and between
  fT4 and PASP, were found.14

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DiscussionBack to this case

• Our patient presented with sudden cardiac arrest,
  clinical hyperthyroidism, pulmonary hypertension,
  and confirmed fenfluramine exposure.
• She had no meaningful neurologic recovery after
  the resuscitation despite optimal hemodynamic
  support and she finally succumbed.
• Differential diagnoses include undiagnosed PAH,
  hyperthyroid heart disease, acute myocardial
  infarction, myocarditis, and massive pulmonary
  embolism.

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Discussion

• Ischemic heart disease and myocarditis were
  unlikely in light of the normal electrocardiogram
  and the fact that the patient had no fever before
  admission.
• The absence of deep vein thrombosis and minimal
  requirement in ventilatory support also
  contraindicated massive pulmonary embolism.
• The significant PAH with AR and MR could be
  explained by the use of fenfluramine.

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Discussion

• Other pathologies, such as chronic rheumatic
  heart disease, were not substantiated by
  echocardiography, which demonstrated
  normal-appearing valves.
• Chronic left to right shunt and chronic lung
  pathology were excluded.
• There was no evidence of connective tissue
  disease or chronic pulmonary disease to suggest a
  secondary cause for PAH.

35
Discussion

• Therefore, primary PAH and valvular heart disease
  due to fenfluramine fit best into the picture.
• This was consistent with the autopsy findings,
  which revealed fibroproliferative plagues in
  pulmonary arteries and mitral and aortic
  valvulopathy with fibromyxoid change.
• These are typical findings of patients exposed to
  fenfluramine-phentermine.10-12

36
Figure 1. Explanted Mitral Valve from Patient 5,
Demonstrating Glistening White Leaflets and
Chordae with Mild-to-Moderate Irregular but
Diffuse Thickening.
Connolly H.M. 1997 NEJM, p581
37
Discussion

• Hyperthyroidism caused further high-output
  cardiac failure and decompensation, but may have
  only been incidental and not responsible for this
  sudden collapse.
• The baseline measurements of antithyroglobulin
  and antimicrosomal antibodies obtained 5 years
  ago were negative.
• Together with the biochemical hyperthyroidism and
  inappropriate low serum thyroglobulin level,
  thyroxine-induced factitious hyperthyroidism was
  suspected.
• However, thyroxine was not identified in the
  culprit weight-loss pills.

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Discussion

• It has become increasingly common for nonobese
  women in Southeast Asia to go on diets.
• A survey of adolescent female students in Hong
  Kong reported that 85 wanted to lose weight,
  although only 4.8 were actually overweight.15
• The prevalence of misuse of diet pills in the
  locality remains unknown.
• Many appetite suppressants were sold as natural
  or herbal health foods that are not subject to
  the Pharmacy and Poisons Ordinance.

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Discussion

• Fenfluramine was de-registered in 1998 in Hong
  Kong, but weight-loss agents containing the drug
  can still be found in the territory.
• Since 2003, more than 14 herbal diet pills
  containing Western medicines have been recalled
  by the health bureau. Six products were found to
  contain fenfluramine.16

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Discussion

• We reported here on a case of fatal pulmonary
  hypertension and valvular heart disease related
  to the use of fenfluramine.
• The culprit weight-loss pill was purchased in
  Mainland China, and is not registered in Hong
  Kong or Macau.
• The Health Bureau was notified.
• The product had no label specifying its
  ingredients.
• In an era of weight-loss obsession, clinicians
  should be alert to the side effects of appetite
  suppressants and diet pills.

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Case Reports Valvular Heart Disease Associated
With Fenfluramine Detected 7 Years After
Discontinuation of Treatment Guillaume Greffe,
MDa, Lara Chalabreysse, MDb, Carine Mouly-Bertin,
MDc, Pierre Lantelme, MD, PhDd, Françoise
Thivolet, MDb, Gilles Aulagner, MDc,
Jean-François Obadia, MD, PhDa, a Department of
Cardiothoracic Surgery, Louis Pradel Hospital,
Lyon, Franceb Department of Cytopathology, Louis
Pradel Hospital, Lyon, Francec Department of
Pharmacy, Louis Pradel Hospital, Lyon, Franced
Department of Cardiology, Croix-Rousse Hospital,
Lyon, France Accepted for publication November
9, 2006, published in, April 2007, Ann.thorac
surg We report the case of a patient referred
to us for mitral and aortic valvular disease with
a rheumatic appearance. The unusual macroscopic
appearance on valve resection was not compatible
with a rheumatic cause. A detailed review of this
patients clinical history (ie, a history of
treatment with fenfluramine) suggested an
iatrogenic cause, which was confirmed by
histology. For the first time, a case of valvular
heart disease that deteriorated was discovered 7
years after treatment with fenfluramine, whereas
this iatrogenic disease classically resolves
after discontinuation of treatment. This case
illustrates the need for continuing heart valve
surveillance of patients who have used these
anorectics.
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Thank you for your attention