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Pulmonary Hypertension Caused by Graves’ Thyrotoxicosis*: Normal Pulmonary Hemodynamics Restored by 131I Treatment FREE TO VIEW

Inaam A. Nakchbandi, MD; Joel A. Wirth, MD, FCCP; Silvio E. Inzucchi, MD
Author and Funding Information

*From the Department of Medicine/Endocrinology, Yale University School of Medicine (Drs. Nakchbandi and Inzucchi), New Haven, CT, and the Maine Medical Center (Dr. Wirth), Portland, ME.

Correspondence to: Inaam A Nakchbandi, MD, Yale University School of Medicine, Department of Medicine/Endocrinology, PO Box 208020, New Haven, CT 06520-8020; e-mail: Endocrine.Fellows@Yale.edu



Chest. 1999;116(5):1483-1485. doi:10.1378/chest.116.5.1483
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We describe a case of pulmonary hypertension, initially thought to be idiopathic, which resolved after treatment of Graves’ hyperthyroidism. Results of pulmonary artery catheterization before and after treatment are reported, and the effects of thyrotoxicosis on hemodynamics and pulmonary function are briefly reviewed. Possible mechanisms for development of pulmonary hypertension caused by hyperthyroidism include pulmonary vascular endothelial dysfunction or damage because of autoimmunity or the high cardiac output state, or increased metabolism of intrinsic pulmonary vasodilators.

Figures in this Article

The cardiovascular manifestations of thyrotoxicosis are profound and characteristic. These include sinus tachycardia, atrial dysrhythmias, increased cardiac output, widened pulse pressure, and occasionally cardiac failure.1Recently, the presence of elevated pulmonary artery pressures by noninvasive testing methods in hyperthyroid patients has been observed.2 We present a patient initially diagnosed with primary pulmonary hypertension, who was later found to be hyperthyroid. Her pulmonary hemodynamics normalized on correction of her hyperthyroidism. Invasive hemodynamic testing, both during thyrotoxicosis and after normalization of thyroid function, are reviewed.

A 46-year-old woman with a past history of hypertension and smoking presented with dyspnea on exertion, peripheral edema, and tachycardia. A chest radiograph demonstrated cardiomegaly and a prominent pulmonary artery (Fig 1 ). Pulmonary function tests showed a moderate restrictive defect with an FVC of 1.33 L (43% of predicted), FEV1 of 1.10 L, FEV1/FVC of 83%, and a carbon monoxide diffusing capacity of 14.87 mL·min−1·mm Hg−1 (76% of predicted). The restrictive defect presumably was at least partly caused by her morbid obesity (weight, 136 kg; height, 157 cm), her small thorax, and the presence of cardiomegaly. An echocardiogram demonstrated right atrial and ventricular dilation with an estimated pulmonary artery systolic pressure of 71 mm Hg (normal, 15 to 30 mm Hg). A thoracic CT failed to reveal definitive parenchymal pulmonary disease. A ventilation/perfusion scan was interpreted as indicating a low probability for pulmonary embolism. Antinuclear antibodies showed a mixed pattern, with a titer of 1:40 uniform pattern and 1:160 nucleolar pattern. The absence of symptoms of autoimmune diseases such as Raynaud’s phenomenon suggested that a diagnosis of collagen vascular disease was unlikely. A diagnosis of primary pulmonary hypertension was made, and the patient was transferred to our institution for pulmonary catheterization and assessment of response to vasodilators. Her baseline hemodynamic testing results are shown in Table 1 .

The presence of an elevated cardiac index and development of atrial fibrillation led to the testing of thyroid function. The results were consistent with pronounced thyrotoxicosis, with a total thyroxine concentration of 20.8 μg/dL (normal, 5.0 to 10.6 μg/dL), free thyroxine index of 6.0 ng/dL (normal, 1.0 to 2.2 ng/dL), and thyroid-stimulating hormone < 0.04 μIU/mL (normal, 0.10 to 6.3μ IU/mL). On examination, the thyroid gland was small without any irregularities. She did not have any stare, lid lag, or proptosis. Auscultation of the lungs revealed clear lung fields, and her cardiac sounds were notable for splitting of both S1 and S2. In addition, she had extensive pitting edema in both lower extremities. A mild fine tremor was observed in both hands, as was mild hyperreflexia. Titers of antithyroglobulin (positive at a titer of 1:2,560; normal, < 1:10), antiperoxidase (556 IU/mL; nonreactive, < 1.5), and thyroid-stimulating hormone (163%; normal,< 130% of basal activity) antibodies were elevated. As a result of these findings, a diagnosis of Graves’ disease was made.

The patient was treated with furosemide, warfarin, metoprolol, and propylthiouracil. Her thyroid function tests improved, and the patient experienced a significant reduction in her dyspnea and edema. After 3 months, however, agranulocytosis developed. In preparation for radioactive ablation, 123I uptake was 87% at 24 h and a technetium thyroid scan showed homogeneous uptake throughout the gland, confirming the diagnosis of Graves’ disease. She was subsequently treated with 15 mCi of 131I. Seven months after initiation of antithyroid therapy, her thyroid function tests were normal with a free thyroxine index of 1.7 (normal, 1.4 to 3.0). A repeat pulmonary artery catheterization showed reversal of her original abnormalities (Table 1). One year after therapy, she remains off medications, is euthyroid, and has no symptoms of pulmonary hypertension or cardiac failure.

Pulmonary hypertension (mean pulmonary artery pressure > 25 mm Hg at rest or > 30 mm Hg during exercise3) may be caused by left ventricular dysfunction, myocardial or valvular disease, congenital heart disease, left atrial myxoma, severe obstructive or restrictive lung disease, sleep-disordered breathing, pulmonary embolism, connective tissue diseases, or anorectic sympathomimetic amines (ie, fenfluramine, etc.). Primary pulmonary hypertension has a prevalence of 0.13%4 and is found at autopsy in approximately 1% of patients with cor pulmonale.5 Typical symptoms include exertional dyspnea, fatigue, substernal chest pain, and exertional or postexertional syncope. Many of these features were exhibited by our patient. Her pulmonary hypertension was believed to be idiopathic until marked abnormality in thyroid function was discovered, which, in retrospect, was the cause of her high-output cardiac failure. The normalization of her intrapulmonary hemodynamics with correction of her thyrotoxicosis strongly suggests a cause and effect relationship between her thyrotoxicosis and her pulmonary hypertension.

Thyrotoxicosis results in major disturbances in both the respiratory and cardiovascular system. Systemic vascular resistance decreases by 50 to 70%,6because thyroid hormone itself acts as a vasodilator. As vascular resistance declines, so does diastolic BP, which results in an increase in heart rate, increased incidence of atrial dysrhythmias, and increased myocardial contractility. Finally, the cardiac index increases by 200 to 300% in thyrotoxicosis because of vasodilation, reflex tachycardia, and increased contractility.7The changes in cardiac physiology may lead to substantial changes in renal physiology, with increased glomerular filtration rate and increased net tubular reabsorption of sodium, the latter of which results in an increase in blood volume of 25%.8 This may result in exacerbation of underlying congestive heart failure.

It is well known that, clinically, hyperthyroidism is associated with dyspnea on exertion. Proposed mechanisms include increased oxygen consumption and carbon dioxide production (from increased metabolic rate).9Although there is no change in airway resistance in hyperthyroid patients, both lung compliance and respiratory muscle strength may be decreased, and both improve with restoration of the euthyroid state.1011

Several associations between the thyroid and pulmonary hypertension have been reported. In their group of 40 patients with primary pulmonary hypertension, Yanai-Landau and colleagues12found that 30% had antithyroglobulin antibodies. This represents an approximate 8-fold increase over the published incidence in the general population.13The explanation for this association is not clear, but antithyroid antibodies may be a marker for generalized immune activation, and may provide a clue to the pathogenesis of some cases of primary pulmonary hypertension. An association between thyrotoxicosis and increased pulmonary artery pressure has been described by Martos Velasco,14Okura and Takatsu,15Alcázar et al,16and Agraou et al,17 who each reported a single patient with elevated mean pulmonary artery pressures (as estimated by Doppler echocardiography) during hyperthyroidism, resolving after antithyroid therapy. Subsequently, Thurnheer et al2 studied four patients with thyrotoxicosis by Doppler echocardiography and found an elevated mean pulmonary artery pressure of 40 ± 11 mm Hg, which decreased to 25 ± 6 mm Hg after achievement of a euthyroid state. Ours is the first reported case of hyperthyroidism and pulmonary hypertension in which invasive hemodynamic testing was performed before and after resolution of the patient’s thyrotoxicosis. It is conceivable that her elevated pulmonary artery pressures were a direct result of high-output cardiac failure. Possible pathogenetic mechanisms for the association between pulmonary hypertension and Graves’ disease include (1) autoimmune phenomenon associated with endothelial damage or dysfunction, (2) increased cardiac output resulting in endothelial injury, and finally (3) increased metabolism of intrinsic pulmonary vasodilating substances.

In summary, several associations between the thyroid and pulmonary hypertension exist, and hyperthyroidism can result in important changes in pulmonary and cardiac functions. Specifically, thyrotoxicosis appears to result in increased pulmonary artery pressures, presumably because of the increase in cardiac output. In our patient, the clinical presentation was initially thought to represent primary pulmonary hypertension. Her hyperthyroidism was only suspected after the results of hemodynamic testing and the new onset of atrial fibrillation. After Graves’ hyperthyroidism was diagnosed and treated, her symptoms resolved and repeat measurement of pulmonary hemodynamics reverted to normal. Hyperthyroidism should be included in the differential diagnosis of pulmonary hypertension. In addition, further investigation into the exact nature of the association between thyroid disease and pulmonary hypertension appears warranted.

Figure Jump LinkFigure 1. Chest radiograph demonstrates cardiomegaly and prominent proximal pulmonary arteries.Grahic Jump Location
Table Graphic Jump Location
Table 1. Hemodynamic Monitoring Before and After Treatment of Hyperthyroidism*
* 

Normal values are given as a range in parentheses. RV = right ventricle; PA = pulmonary artery; MPAP = mean pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; CI = cardiac index; PVR = pulmonary vascular resistance.

Sandler, G, Wilson, GM (1959) The nature and prognosis of heart disease in thyrotoxicosis.Q J Med28,347-368. [PubMed]
 
Thurnheer, R, Jenni, R, Russi, EW, et al Hyperthyroidism and pulmonary hypertension.J Intern Med1997;242,185-188. [PubMed] [CrossRef]
 
Rubin, LJ, Barst, RJ, Kaiser, LR, et al Primary pulmonary hypertension.Chest1993;104,236-250. [PubMed]
 
McDonnell, PJ, Toye, PA, Hutchins, GM Primary pulmonary hypertension and cirrhosis: are they related?Am Rev Respir Dis1983;127,437-441. [PubMed]
 
Rich, S, Brundage, BH Primary pulmonary hypertension: current update.JAMA1984;251,2252-2254. [PubMed]
 
Klemperer, JD, Klein, I, Gomez, M, et al Thyroid hormone treatment after coronary artery bypass surgery.N Engl J Med1995;333,1522-1527. [PubMed]
 
Klein, I Thyroid hormone and the cardiovascular system.Am J Med1990;88,631-637. [PubMed]
 
Klein, I, Levey, GS The cardiovascular system in thyrotoxicosis. Braverman, LE Utiger, RD eds.Werner and Ingbar’s the thyroid 7th ed.1996,607-615 Lippincott-Raven. Philadelphia, PA:
 
Zwillich, CW, Matthay, M, Potts, DE, et al Thyrotoxicosis: comparison of effects of thyroid ablation and β-adrenergic blockade on metabolic rate and ventilatory control.J Clin Endocrinol Metab1978;46,495-500
 
Stein, M, Kimbel, P, Johnson, RL Pulmonary function in hyperthyroidism. J Clin Invest. 1961;;40 ,.:348. [PubMed]
 
Mier, A, Brophy, C, Wass, JAH, et al Reversible respiratory muscle weakness in hyperthyroidism.Am Rev Respir Dis1989;139,529-533. [PubMed]
 
Yanai-Landau, H, Amital, H, Bar-Dayan, Y, et al Autoimmune aspects of primary pulmonary hypertension.Pathobiology1995;63,71-75. [PubMed]
 
Amino, N, Tada, H Autoimmune thyroid disease/thyroiditis. DeGroot, LJ eds.Endocrinology 3rd ed.1995,726-741 WB Saunders. Philadelphia, PA:
 
Martos Velasco, J Primary pulmonary hypertension associated with hyperthyroidism (Spanish).Aten Primaria1992;9,163-164. [PubMed]
 
Okura, H, Takatsu, Y High-output heart failure as a cause of pulmonary hypertension.Intern Med1994;33,363-365. [PubMed]
 
Alcázar, R, Rey, M, de Sequera, P, et al The reversibility of pulmonary hypertension associated with autoimmune hyperthyroidism (Spanish).Rev Esp Cardiol1995;48,142-144. [PubMed]
 
Agraou, B, Tricot, O, Strecker, A, et al Hyperthyroidism associated with pulmonary hypertension (French).Arch Mal Coeur Vaiss1996;89,765-768. [PubMed]
 

Figures

Figure Jump LinkFigure 1. Chest radiograph demonstrates cardiomegaly and prominent proximal pulmonary arteries.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Hemodynamic Monitoring Before and After Treatment of Hyperthyroidism*
* 

Normal values are given as a range in parentheses. RV = right ventricle; PA = pulmonary artery; MPAP = mean pulmonary artery pressure; PCWP = pulmonary capillary wedge pressure; CI = cardiac index; PVR = pulmonary vascular resistance.

References

Sandler, G, Wilson, GM (1959) The nature and prognosis of heart disease in thyrotoxicosis.Q J Med28,347-368. [PubMed]
 
Thurnheer, R, Jenni, R, Russi, EW, et al Hyperthyroidism and pulmonary hypertension.J Intern Med1997;242,185-188. [PubMed] [CrossRef]
 
Rubin, LJ, Barst, RJ, Kaiser, LR, et al Primary pulmonary hypertension.Chest1993;104,236-250. [PubMed]
 
McDonnell, PJ, Toye, PA, Hutchins, GM Primary pulmonary hypertension and cirrhosis: are they related?Am Rev Respir Dis1983;127,437-441. [PubMed]
 
Rich, S, Brundage, BH Primary pulmonary hypertension: current update.JAMA1984;251,2252-2254. [PubMed]
 
Klemperer, JD, Klein, I, Gomez, M, et al Thyroid hormone treatment after coronary artery bypass surgery.N Engl J Med1995;333,1522-1527. [PubMed]
 
Klein, I Thyroid hormone and the cardiovascular system.Am J Med1990;88,631-637. [PubMed]
 
Klein, I, Levey, GS The cardiovascular system in thyrotoxicosis. Braverman, LE Utiger, RD eds.Werner and Ingbar’s the thyroid 7th ed.1996,607-615 Lippincott-Raven. Philadelphia, PA:
 
Zwillich, CW, Matthay, M, Potts, DE, et al Thyrotoxicosis: comparison of effects of thyroid ablation and β-adrenergic blockade on metabolic rate and ventilatory control.J Clin Endocrinol Metab1978;46,495-500
 
Stein, M, Kimbel, P, Johnson, RL Pulmonary function in hyperthyroidism. J Clin Invest. 1961;;40 ,.:348. [PubMed]
 
Mier, A, Brophy, C, Wass, JAH, et al Reversible respiratory muscle weakness in hyperthyroidism.Am Rev Respir Dis1989;139,529-533. [PubMed]
 
Yanai-Landau, H, Amital, H, Bar-Dayan, Y, et al Autoimmune aspects of primary pulmonary hypertension.Pathobiology1995;63,71-75. [PubMed]
 
Amino, N, Tada, H Autoimmune thyroid disease/thyroiditis. DeGroot, LJ eds.Endocrinology 3rd ed.1995,726-741 WB Saunders. Philadelphia, PA:
 
Martos Velasco, J Primary pulmonary hypertension associated with hyperthyroidism (Spanish).Aten Primaria1992;9,163-164. [PubMed]
 
Okura, H, Takatsu, Y High-output heart failure as a cause of pulmonary hypertension.Intern Med1994;33,363-365. [PubMed]
 
Alcázar, R, Rey, M, de Sequera, P, et al The reversibility of pulmonary hypertension associated with autoimmune hyperthyroidism (Spanish).Rev Esp Cardiol1995;48,142-144. [PubMed]
 
Agraou, B, Tricot, O, Strecker, A, et al Hyperthyroidism associated with pulmonary hypertension (French).Arch Mal Coeur Vaiss1996;89,765-768. [PubMed]
 
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