Hypothyroidism and Primary Pulmonary Hypertension: An Autoimmune Pathogenetic Link?

Primary pulmonary hypertension (PPH) is an often fatal disease of unknown cause that primarily affects young women [1]. The relative roles of genetic predisposition, autoimmunity, viral infection, hormonal influences, and environmental and drug exposures are not known. Clinical associations may suggest common underlying etiologic mechanisms. We report four cases of PPH in female patients with low-titer positive antinuclear antibodies (ANA) and hypothyroidism, raising the possibility of an autoimmune pathogenetic link. Case Reports Patient 1 Exertional dyspnea developed in a 42-year-old Hispanic woman after a laparoscopic cholecystectomy in July 1991. In October 1991 chest radiography showed cardiomegaly and enlarged pulmonary arteries. Echocardiography, pulmonary function testing, a ventilation-perfusion lung scan, and a sleep study were consistent with PPH. Cardiac catheterization showed pulmonary arterial pressures of 80/48 mm Hg. The woman's sister had mixed connective tissue disease. Medications included enalapril, warfarin, and supplemental oxygen. An ANA study was low-titer positive. Catheterization results from February 1992 are shown in Table 1. She entered the prostacyclin trial and was randomized to conventional therapy. In March 1992 she developed right-sided congestive heart failure with ascites and massive peripheral edema, jaundice, elevated liver function tests, a more prolonged prothrombin time, and depression. Results of hepatitis serologic tests were negative. Her thyroid-stimulating hormone (TSH) level was 11 mU/L (normal range, 0.5 to 5 mU/L). Low-dose thyroid supplementation (0.025 mg/d) was begun, and her TSH returned to normal in 1 to 2 weeks. Her clinical condition deteriorated and she died in April 1992. An autopsy showed plexiform lesions of the pulmonary arteries consistent with PPH, chronic hepatic congestion, and chronic thyroiditis with fibrosis and follicular atrophy. Table 1. Collagen Vascular Screen and Hemodynamic Data* Patient 2 A 45-year-old white woman had progressive fatigue and exertional dyspnea before 1988, when cardiac catheterization revealed a systolic pulmonary arterial pressure of 120 mm Hg. She had Raynaud phenomenon, a positive result of ANA, and carpal tunnel syndrome. Hypothyroidism had been diagnosed in 1965 and thyroid supplementation begun. Medications in March 1992 included nicardipine, furosemide, potassium supplementation, warfarin, thyroid supplementation, alprazolam, and albuterol and ipratropium bromide inhalers. She had an increased pulmonic closure sound, jugular venous distention, and pitting edema of the lower extremities. Chest radiography, ventilation-perfusion lung scan, echocardiography, and pulmonary function testing were consistent with PPH. A sleep study showed mild nonapneic desaturation. Result of an ANA was low-titer positive. Catheterization results from March 1992 are shown in Table 1. She entered the prostacyclin study, was randomized to prostacyclin plus conventional therapy, and is awaiting lung transplantation. Patient 3 A 33-year-old white woman became ill in 1988 during hospitalization for delivery of her second child. Postpartum cardiac catheterization revealed pulmonary hypertension. Result of an ANA was low-titer positive (Table 1). Her condition worsened, and in July 1991 thyroid tests revealed a TSH of 150 U/L (normal range, 0.5 to 5.0 U/L) and a T4 of 28.3 nmol/L (normal range, 63.1 to 157 nmol/L). Thyroid supplementation was begun at 0.05 mg daily and was increased to 0.088 mg daily. In December 1991 fluid retention, ascites, cyanosis, and worsening exertional dyspnea developed. In January 1992 she had hypotension, perioral and peripheral cyanosis, murmurs of tricuspid and pulmonic insufficiency, jugular venous distention, ascites, pitting edema of the lower extremities, and venous stasis changes. Chest radiography, pulmonary function testing, echocardiography, and a ventilation-perfusion lung scan were consistent with PPH. She was catheterized in January 1992 (see Table 1). She entered the prostacyclin study and was randomized to conventional therapy. Her condition improved with oxygen, warfarin, furosemide, and spironolactone treatment. Twelve weeks later she began prostacyclin [on a continuation study] in addition to her conventional therapy, and she had a single-lung transplantation in December 1992. Patient 4 A 53-year-old white woman noted exertional dyspnea and Raynaud phenomenon in autumn 1990 following nonspecific encephalitis. Echocardiography revealed severe pulmonary hypertension with right ventricular dysfunction. A ventilation-perfusion lung scan was read as being low probability for pulmonary emboli. Catheterization in December 1990 showed pulmonary arterial pressures of 50/25 mm Hg. Her medical history included spontaneous pneumothorax in 1958, reactive airway disease as a child, seasonal rhinitis, systemic hypertension during the past 2 years, and left lower lobe pneumonia in January 1991. Medications in March 1992 included diltiazem, lisinopril, hydrochlorothiazide, and guanfacine. She had mild systemic hypertension, an accentuated pulmonic heart sound, hepatojugular reflux, mild hepatomegaly, and pitting edema of the ankles. An ANA result was low-titer positive (see Table 1). Chest radiography, pulmonary function testing, echocardiography, and a ventilation-perfusion lung scan were consistent with PPH. She was catheterized in May 1992 (see Table 1). She entered the prostacyclin study and was randomized to receive prostacyclin plus conventional therapy. Thyroid tests in May 1992 (before prostacyclin) showed a TSH of 45 mU/L (normal range, 0.5 to 5.0 mU/L), T4 of 12.87 nmol/L (normal range, 51.5 to 154 nmol/L), and a T3 uptake of 0.38 (normal range, 0.25 to 0.35). Thyroid supplementation was begun. She is awaiting lung transplantation. Discussion We report four cases of hypothyroidism in female patients with severe PPH. Two had elevated TSH levels at our center and two were previously diagnosed and received thyroid supplementation elsewhere. All four patients were women with low-titer-positive ANAs and severe pulmonary hypertension in the absence of secondary causes. Two had Raynaud phenomenon. One woman was diagnosed with hypothyroidism before PPH was diagnosed. Except for a single case of chronic thyroiditis associated with pulmonary hypertension reported from Japan in 1968 [2], we believe this is the first report of a possible association between PPH and hypothyroidism. Thyroid dysfunction is frequently of autoimmune causes and is associated with other autoimmune diseases. Abnormal thyroid tests are common in patients with systemic lupus erythematosus [3]. Elevation of anti-DNA antibody titer has been reported during the thyrotoxic phase of silent thyroiditis [4] and in Grave disease [5]. Autoimmune thyroiditis occurs in scleroderma [6] and the Sjogren syndrome [7]. Pulmonary hypertension has been associated with autoimmune diseases including scleroderma, systemic lupus erythematosus, and mixed connective tissue disease [8-10]. Low-titer-positive ANAs occur in patients with PPH [1, 11]. Autoantibodies to Ku, a DNA-binding protein, which are found in some cases of systemic lupus erythematosus, scleroderma, myositis, and the Sjogren syndrome, have recently been reported in a subset of patients (23%) with PPH [12]. An autoimmune pathogenetic link between hyperthyroidism and PPH was proposed in the report of a single case [13]. Coexistence of hypothyroidism and PPH also raises the possibility of an underlying autoimmune process, which may be an important clue to the cause of PPH in this subgroup of patients. Raynaud phenomenon occurs in PPH [1] and in hypothyroidism, where it has been shown to improve with thyroid supplementation [14-16], suggesting a causal relationship [15]. Pulmonary artery vasospasm may precede chronic pulmonary hypertension and play an etiologic role [17]. Thus, thyroid hormone may play a vascular stabilizing role and thyroid insufficiency could contribute to vasospasm in Raynaud phenomenon and pulmonary hypertension. An association between PPH and hypothyroidism might be important for several reasons: It suggests an underlying autoimmune process contributing to both disorders; thyroid insufficiency could contribute to vasoconstriction; and monitoring of thyroid function may be indicated in PPH to avoid underdiagnosis of hypothyroidism. A prospective study is needed to validate our findings but may require considerable time to complete given the low prevalence of primary pulmonary hypertension.