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Pulmonary Hypertension, Hyperthyroidism,

and Fenfluramine: A Case Report and ReviewFrom Medscape General Medicine

Posted 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 ofhyperthyroidism (5 yearsprior) 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.


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Case Report

She was not known to be taking long-termmedications, but had been short-tempered and hadsignificant 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 regurgitationmurmur.

Chest radiography showed cardiomegalyand mild congestion.


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Case Report

Brain computer tomography revealed cerebraledema that is compatible with hypoxic brain damage.

Electrocardiogram post resuscitation showed sinusrhythm without ischemic change. Creatinine kinase

was only slightly elevated to 387 IU/L (normal range,48-197 IU/L).

Serum antinuclear antibody titer was 1:80.

Blood tests were compatible with hyperthyroidism

with thyroid stimulating hormone (TSH) and freethyroxine (fT4), < 0.02 mIU/L (normal range, 0.27-4.20mI/L) and 30.4 pmol/L (normal range, 12.0 - 22.0pmol/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 of220/100 mm Hg and 100 beats perminute, 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 hemodynamicdeterioration requiring inotrope support.

Echocardiography revealed an ejection fraction of87% without regional wall abnormality, a

predominance ofright heart failure, and moderateaortic regurgitation (AR) and mitral regurgitation(MR), without leaflet thickening and rightventricular dilatation.

Significant PAH (pulmonary artery hypertension)was confirmed, with the pulmonary arterial systolicpressure (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 ofweight-loss pills from her room,

which tested positive for fenfluramine.

Fenfluramine derivatives were also detectedin the patient's first urine sample.

Serum thyroglobulin was 21mcg/L, which is

inappropriately low, suggesting anexogenous 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 ofvasoactivemediators.


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Discussion

Patients with PAH have an excess ofvasoconstrictive mediators such as endothelin-1,thromboxane, and serotonin in the pulmonaryvascular bed, and the production ofvasodilatorssuch as prostacyclin and nitric oxide is impaired.

These abnormalities promote downstreaminflammation, activation of cytokines, andvascular remodeling.

The end result is vasoconstriction, followed byvascular intimal proliferation and fibrosis, in situthrombosis, and plexigenic arteriopathy.


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Marc Humbert et al 2004 NEJM p1425


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Discussion

PAH is defined as

a mean PASP > 25 mm Hg at rest or > 30 mm Hg

during exercise.

The Doppler echocardiography definition of PAHis based on tricuspid regurgitation jet > 2.8

m/sec.[2]

PAH is classified as primary or secondary

according to World Health Organization(WHO) criteria.


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Marc Humbert et al2004 NEJM p1425


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2003 Lancet, Runo J.R. p1533


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Discussionsympathomimetics and PAH

Fenfluramine derivatives, includingfenfluramine and dexfenfluramine, aresympathomimetics.

They exert an anorexic action by activatingthe serotonin pathway in the brain.

Serotonin is itself a potent vasoconstrictorand can induce platelet aggregation.

It also interacts with 5-hydroxytryptamine (5-HT) receptors and promotes pulmonaryvascular smooth muscle proliferation.[3]


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Farber H.W. et al 2004 NEJM P1655


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Discussion

The mechanism responsible for the development ofPAH in patients exposed to fenfluramine is unclear.

Weir and colleagues[4] 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.


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Adrogu H.J. and Madias N.E.

NEJM 2007(356):1966-1978,


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NEJM 2007(356):1966-1978,


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NEJM 2007(356):1966-1978,


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NEJM 2007(356):1966-1978,


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Farber H.W. et al 2004 NEJM P1655


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Discussion

In the early 1990s, a cluster of cases of PAH was reportedamong patients who had used derivatives of fenfluramine.[5]

Subsequent study confirmed a causal relationship betweenfenfluramine 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 ofany appetite suppressant within the previous year wasassociated with a 10-fold increase in the development ofPAH.[7]

The risk further increased to > 20-fold with usage of the drugfor more than 3 months.

The majority of patients had used fenfluramine anddexfenfluramine 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 ofPrimary Pulmonary Hypertension supported

by the National Heart, Lung, and Blood

Institute.

In the study by Simmoneau and colleagues, theoverall survival offenfluramine-induced PAH

was as poor as that ofprimary PAH.[3]


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Discussion

sympathomimetics and VHD The most commonly reported valvulopathy

among patients exposed to fenfluramine areAR and MR, and the risk correlated to theduration of exposure.

The relative risk ratios ofAR and MRwere2.32 (95% confidence intervals 1.79 to 3.01,

P < .00001) and 1.55 (95% confidenceintervals 1.06 to 2.25, P= .02), respectively, ina meta-analysis involving 1279 patientsexposed 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.

Photographcourtesy of James R.

Stone, M.D., Ph.D.,

Department of

Pathology,

Brigham andWomens Hospital,

Boston.

KULKE M.H. 1999 NEJM, p858


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Connolly H.M. 1997 NEJM, p581,

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-onplaques (arrows).

In Panel B, a high-power view

(hematoxylin and eosin, 360)

shows proliferativemyofibroblasts in an

abundant extracellular matrix


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Bryan L. Roth, 2007 NEJM,

p6-9


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Discussion

Hyperthyroidism and CV system

Hyperthyroidism affects the cardiovascularsystem in several ways.

It plays a role in sinus tachycardia, atrialfibrillation, decreased exercise tolerance,dilated cardiomyopathy, and, in some cases,high-output congestive heart failure.

PAH related to hyperthyroidism has beenreported.

Resolution of PAH after successful treatment ofhyperthyroidism has also been demonstrated.


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Discussion

Hyperthyroidism and PAH

Several mechanisms have been suggested in thepathogenesis, including an autoimmune processleading to pulmonary endothelial damage ordysfunction; increased cardiac output causing

pulmonary endothelial injury; and increasedmetabolism of intrinsic pulmonary vasodilatingsubstances.[12]

A transthoracicDoppler echocardiography study ina cohort of patients with Graves' disease reportedmild PAH in 7 out of 17 patients.

Correlations between TSH and PASP, and betweenfT4 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 afterthe resuscitation despite optimal hemodynamic

support and she finally succumbed.

Differential diagnoses include undiagnosed PAH,

hyperthyroid heart disease, acute myocardialinfarction, myocarditis, and massive pulmonary

embolism.


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Discussion

Ischemic heart disease and myocarditiswere unlikely in light of the normalelectrocardiogram and the fact that thepatient had no fever before admission.

The absence ofdeep vein thrombosis andminimal requirement in ventilatory supportalso contraindicated massive pulmonary

embolism. The significant PAH with AR and MR

could be explained by the use offenfluramine.


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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 ofconnective tissue

disease or chronic pulmonary disease to suggesta secondary cause for PAH.


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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]


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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


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Discussion

Hyperthyroidism caused further high-outputcardiac failure and decompensation, but may haveonly been incidental and not responsible for thissudden collapse.

The baseline measurements ofantithyroglobulinand antimicrosomal antibodies obtained 5 yearsago were negative.

Together with the biochemical hyperthyroidismand inappropriate low serum thyroglobulin level,

thyroxine-induced factitious hyperthyroidism wassuspected.

However, thyroxine was not identified in theculprit 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 productswere found to contain fenfluramine.[16]


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Discussion

We reported here on a case of fatal pulmonaryhypertension and valvular heart disease related tothe use of fenfluramine.

The culprit weight-loss pill was purchased inMainland China, and is not registered in HongKong or Macau.

The Health Bureau was notified.

The product had no label specifying its ingredients.

In an era ofweight-loss obsession, cliniciansshould be alert to the side effects of appetitesuppressants 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, Franoise Thivolet, MDb, Gilles Aulagner, MDc, Jean-Franois Obadia, MD, PhDa,*

a Department of Cardiothoracic Surgery, Louis Pradel Hospital, Lyon, France

b Department of Cytopathology, Louis Pradel Hospital, Lyon, France

c Department of Pharmacy, Louis Pradel Hospital, Lyon, France

d 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 aniatrogenic 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

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2007-5-18benh an dot tu cuong giap