Pulmonary hypertension, hyperthyroidism and ...

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Jun 21, 2005 - Pulmonary arterial hypertension (PAH) associated with fenfluramine is well documented and its .... Pulmonary veno-occlusive disease.
Pulmonary hypertension, hyperthyroidism and fenfluramine: A case report and review. Leung YY, Tang KS, Tsang CC, Chan CK, Wong KK, Yu AW. Department of Medicine and Geriatrics, Tai Po Hospital, 9 Chuen On Road, Taipo, NT, Hong Kong SAR Leung Ying Ying

MBChB, MRCP (UK)

Department of Medicine, Alice Ho Miu Ling Nethersole Hospital, 11 Chuen On Road, Taipo, NT, Hong Kong SAR Tsang Chiu Chi

MBBS, FHKAM (Medicine)

Chan Chi Kin

FRCP, FHKAM (Medicine)

Wong Kwan Keung

FRCP (Edin), FHKAM (Medicine)

Yu Alex Wai-yin

FRCP (Edin), FACP

Department of Medicine, Tuen Mun Hospital, Tsing Chung Koon Road, Tuen Mun, NT, Hong Kong SAR Tang Kam Shing

MBBS, FHKAM (Medicine)

Correspondence to: Dr Leung Ying Ying (e-mail: [email protected]), phone: 26076111, Fax: 21441232

Abstract We report a case of pulmonary hypertension presenting with sudden cardiac arrest, hyperthyroidism and fenfluramine usage. This fatal case of pulmonary hypertension and valvular heart disease is associated with the use of an anorexic drug that had been withdrawn from the market more than eight years ago. The awareness of the side effects of slimming agents should be aroused. The association between pulmonary hypertension in relation to hyperthyroidism and fenfluramine usage is reviewed. Keywords: pulmonary hypertension; hyperthyroidism; fenfluramine; anorexic drugs

Introduction Pulmonary arterial hypertension (PAH) associated with fenfluramine is well documented and its association with hyperthyroidism has been described. We hereby report a case of pulmonary hypertension presenting with sudden cardiac arrest and is associated with both hyperthyroidism and fenfluramine usage.

Case report A 53-year-old lady was admitted to the intensive care unit on 21st Jun 2005 for sudden cardiac arrest. She had a history of hyperthyroidism 5 years ago and defaulted follow up. According to her family, she had 2-week history of exertional shortness of breath. On day of admission, she developed sudden increase in dyspnea at home and collapsed shortly afterwards. 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 grossly obese. There was no goiter, signs of connective tissue diseases or deep vein thrombosis. Chest examination was normal. Heart examination reviewed a mitral regurgitation murmur. Chest radiography showed cardiomegaly and mild congestion. Brain computer tomography revealed cerebral edema that is compatible with hypoxic brain damage. Electrocardiogram post resuscitation showed sinus rhythm without ischaemic change. Creatinine-kinase was only slightly elevated to 387 IU/L (normal range, 48 –197 IU/L). Serum anti-nuclear antibody titer was 1:80. Blood tests were compatible with hyperthyroidism with thyroid stimulating hormone (TSH) and fT4, < 0.02 mIU/L (normal range, 0.27 - 4.20mI/L) and 30.4 pmol/L (normal range, 12.0 - 22.0 pmol/L) respectively. Two hours after successful resuscitation, the patient had persistent hypertension and tachycardia, with blood pressure and pulse rate of 220/100 mmHg and 100 beats per minute respectively. She was treated with propylthiouracil, Lugol’s iodine solution and hydrocortisone. She remained unconscious. Five hours later, she had haemodynamic deterioration requiring inotrope support. Echocardiography reviewed an ejection fraction of 87% without regional wall abnormality. There was a predominance of right heart failure. There were moderate aortic regurgitation (AR) and mitral regurgitation (MR), without leaflet thickening and right ventricular dilatation. Significant PAH was confirmed, with the pulmonary arterial systolic pressure (PASP) grossly elevated to 70 mmHg. She ran a downhill course and succumbed 5 days later. Autopsy examination confirmed cor pulmonale secondary to pulmonary hypertension; mitral and aortic valvulopathy. Subsequently, patient’s family found bottles of slimming pill from her room, which tested positive for fenfluramine. Fenfluramine derivatives were also detected in patient’s first urine sample. Serum thyroglobulin was 21μg/L, which is inappropriately low, suggesting an exogenous source of thyroxine leading to hyperthyroidism.

Discussion 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 and with some triggering stimulus, leading to an imbalance of vasoactive mediators. There are excessive vasoconstrictive mediators like endothelin-1, thromboxane and serotonin in the pulmonary vascular bed; while the production of vasodilators like 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.1 PAH is defined as a mean PASP >25mmHg at rest or >30mmHg during exercise. The Doppler echocardiography definition of PAH is based on triscupid regurgitation jet > 2.8m/sec.2 PAH is classified as primary or secondary according to the WHO criteria (Table 1). A diagnosis of primary PAH is made when secondary causes are excluded. 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 Only a minority of patients exposed to fenfluramine derivatives develop PAH, although the true prevalence remains unknown. This suggests a genetic susceptibility in a subset of population. In the early 1990s, a cluster of cases of PAH was reported among patients who had used derivatives of fenfluramine.4 Subsequent study confirmed a causal relationship between fenfluramine with PAH and valvular heart disease, leading to its withdrawal from global market in 1997.5 In a multi-center case-controlled study in Europe, the use of any anorexic drug within the previous year was associated with a 10-fold increase in development of PAH.6 The risk further increased to >20-fold with usage of more than 3 months. Majority of patients had used fenfluramine and dexfenfluramine in this study. The most commonly reported valvulopathy among patients exposed to fenfluramine are AR and MR, with a correlation to the duration of exposure. The relative risk ratios of AR and MR are 2.32 (95% confidence intervals 1.79 to 3.01, p< 0.00001) and 1.55 (95% confidence intervals 1.06 to 2.25, p= 0.02) respectively in a meta-analysis involving 1279 patients exposed to fenfluramine.7 Hyperthyroidism affects the cardiovascular system in several ways. These include sinus tachycardia, atrial fibrillation, decreased exercise tolerance, dilated cardiomyopathy and in some cases, high output congestive heart failure. In recent years, PAH related to hyperthyroidism has been reported. Resolution of PAH after successful treatment of hyperthyroidism was also demonstrated.8-9 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.8 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 fT4 and PASP were found.10 Our patient presented with sudden cardiac arrest, clinical hyperthyroidism and confirmed fenfluramine exposure. Differential diagnoses include undiagnosed pulmonary hypertension, hyperthyroid heart disease, acute myocardial infarction, myocarditis and massive pulmonary embolism. Ischaemic heart disease and myocarditis were unlikely with normal electrocardiogram and no fever before admission. The absence of deep vein thrombosis and minimal requirement in ventilatory support also spoke against massive pulmonary embolism. The significant PAH with AR and MR could be explained by the use of fenfluramine. Other pathology like chronic rheumatic heart disease was not substantiated with normal looking valves on echocardiography. 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 of a secondary cause for PAH. Primary PAH and valvular heart disease due to fenfluramine fit best into the picture. This was consistent with the autopsy findings, which revealed mitral and aortic valvulopathy with fibromyxoid change. This is typical of fenfluramine-phentermine valvulopathy.11 Hyperthyroidism caused further high output cardiac failure and decompensation, but may not be the major cause of sudden collapse. The baseline anti-thyroglobulin and anti-microsomal antibodies taken 5 years ago were negative. Together with the biochemical hyperthyroidism and inappropriate low serum thyroglobulin level, a factitious hyperthyroidism as a result of using thyroxine as slimming agent was suspected. Even-though thyroxine was not identified in the culprit slimming pills.

It has become increasingly common for non-obese women in Hong Kong Special Administrative Region (HKSAR) to go slimming. A survey on adolescent female students reported 85% wanted to lose weight, although only 4.8% were actually overweight.12 The prevalence of misuse of slimming products in HKSAR remains unknown. Many slimming products were sold as natural or herbal health foods that are not subject to the Pharmacy and Poisons Ordinance. Fenfluramine was deregistered in 1998 in HKSAR, but slimming products containing the drug can still be found in the territory. Since 2003, more than 14 herbal slimming products containing Western medicines have been recalled by the health bureau. Six products were found to contain fenfluramine.13 We hereby report a case of fatal pulmonary hypertension and valvular heart disease related to the use of fenfluramine. The culprit slimming pill was bought in mainland China, and the HKSAR health bureau was notified. In an era of craze for slimming, clinicians should alert to the side effects of slimming agents.

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Acknowledgements

We are indebted to staff members of Laboratories of Alice Ho Miu Ling Nethersole Hospital, Prince of Wales Hospital and Department of Health; to Dr Emily Kun of Department of Medicine & Geriatrics, Taipo Hospital for assistance in the preparation of the manuscript.

Table 1. WHO classification of pulmonary hypertension.2 1. Pulmonary arterial hypertension (PAH) Sporadic (IPAH) Familial (FPAH) Association with: • Collagen vascular disease • Congenital systemic-to-pulmonary shunts • Portal hypertension • HIV infection • Drugs and toxins • Other: HHT, hemoglobinopathies, etc. PAH with Significant venous or capillary involvement • Pulmonary veno-occlusive disease • Pulmonary capillary hemangiomatosis Persistent pulmonary hypertension of the newborn 2. Pulmonary venous hypertension 3. Pulmonary hypertension associated with hypoxemia • Chronic obstructive pulmonary disease • Interstitial lung disease • Sleep-disordered breathing • Alveolar hypoventilation disorders • Chronic exposure to high altitudes • Developmental abnormalities 4. Pulmonary hypertension due to chronic thrombotic and/or embolic disease 5. Miscellaneous: Sarcoidosis, histiocytosis X, etc.