Hyperthyroidism and pulmonary hypertension

Journal of Internal Medicine 1997; 242: 185188

1997 Blackwell Science Ltd 185

Abstract. Thurnheer R, Jenni EW, Russi P, GremingerP, Speich R (Department of Internal Medicine,University Hospital, Zrich, Switzerland). Hyper-thyroidism and pulmonary hypertension (Casereport). J Intern Med 1997; 242: 1858.

Objectives. To identify patients with hyperthyroidismand coincidental pulmonary hypertension and todocument reversibility of pulmonary hypertensionafter treatment of hyperthyroidism.Design. Patients with hyperthyroidism referred fortransthoracal echocardiography for any reason thatshowed elevated pulmonary arterial pressures werecollected. After therapy for the thyreotoxic state withdocumented normalization of thyroid hormone(fT4), pulmonary arterial pressure was measuredagain noninvasively.Setting. An out-patient tertiary referral centre.Subjects. The medical records were used to identify,retrospectively, patients with hyperthyroidism andpulmonary hypertension over a three-year period

(April 1993 to April 1996).Interventions and main outcome measures. Systolicpulmonary artery pressure (PAPs) was determinedby adding up right ventricular systolic pressure(RVSP) and mean right atrial pressure (RAP) mea-sured by continuous-wave Doppler echocardiographyaccording to standard techniques. All patients weretreated for hyperthyroidism to normal fT4 levels.After successful therapy, Doppler echocardiographywas repeated.Results. Four patients with pulmonary hypertensionshowing elevated PAPs of 40 6 11 mmHg were iden-tified. After therapy, PAPs decreased in all patients toa mean of 25 6 6 mmHg.Conclusion. The observation of four patients withpulmonary hypertension and hyperthyroidism isstriking and suggests a possible pathogenetic link ofthese disorders.

Keywords: hyperthyroidism, pulmonary hyperten-sion.

Introduction

Primary pulmonary hypertension (PPH) is a rare,progressive, and often fatal disease of unknowncause [1]. The incidence of PPH is increased in vari-ous clinical settings such as autoimmune diseases[2], liver cirrhosis with portal hypertension [3], HIVinfection [4], or use of anorectic agents [5]. Clinicalconditions associated with PPH may help to findcommon underlying aetiologic mechanisms or eluci-date its pathogenesis.

Cardiovascular manifestations are frequent find-

ings in hyper- and hypothyroidism. Herein, we reportfour cases with hyperthyroidism and coincidentalpulmonary hypertension. After successful therapy ofthe thyrotoxic state, the pulmonary arterial pressuredecreased markedly in all patients, indicating a possi-ble pathogenetic link.

Patients and methods

Over a 3-year period (April 1993 to April 1996), themedical records of the University Hospital of Zurichwere used to identify a subset of patients with hyper-

CASE REPORT

Hyperthyroidism and pulmonary hypertensionR. THURNHEER, R. JENNI, E .W. RUSSI, P. GREMINGER & R. SPEICHFrom the Department of Internal Medicine, University Hospital Zrich, Switzerland

R. THURNHEER et al.186

1997 Blackwell Science Ltd Journal of Internal Medicine 242: 185188

thyroidism. Because of our index patient (case 1),patients with hyperthyroidism were examined irre-spective of symptoms of right heart failure. Rightventricular systolic pressure (RVSP) was calculatedfrom the pressure gradient between the right ventri-cle and atrium measured by continuous-waveDoppler echocardiography according to standardtechniques [6]. CVP was not elevated on clinicalexamination and therefore assumed to be 5 mmHg[7]. Mean right atrial pressure is equivalent to CVP[7]. Moreover, normal mean RAP of 5 mm Hg wasconfirmed in all patients using the caval respiratoryindex exceeding 50% as described by Kirchner et al.[8]. PAPs was calculated by adding up RAP andRVSP.

Patients were examined for roentgenographicsigns of pulmonary hypertension, i.e. right descend-ing pulmonary artery diameter of .1.5 cm, andelectrocardiographic features of right ventricularhypertrophy (i.e. right axis deviation 1100 and R/Sratio .1 in V1). Lung perfusion scans were per-formed with 120 Mbq 99 m Tc macroaggregatedalbumin particles. Chronic obstructive and intersti-tial lung disease were ruled out by routine pul-monary function tests. Anti- thyreoglobulinantibodies (reference range 0350 IE mL21) and anti-microsomal antibodies (reference range 0350IE mL21) were measured by enzymeimmunoassayaccording to the manufacturers guidelines(SYNELISA; Elias Medizinische Technik GmbH,Freiburg i. Brsg., Germany), TSI was measured by aradioimmunoassay (TRAKassay, CIS, France, refer-ence range 010% Inhibition). TSH (reference range0.14.0 mU L21) and fT4 (reference range 8.519pmol L21) were measured by chemiluminescence

immunoassays. Results are expressed as mean6 SD.

Results

Four patients, mean age 38 (2779) years with ele-vated mean PAPs 40 6 11 mmHg were detected(Table 1). Patients presented with typical symptomsof hyperthyroidism, only patient 3 showed signs ofmild right heart failure. Left ventricular systolic func-tion was normal in all patients. There was no evi-dence of congenital heart disease, valvular disease orcardiomyopathy, nor suspicion of collagen vascularor liver disease. The patients gave no history of inges-tion of anorectic agents or risk behaviour for HIVinfection. All patients had neither roentgenographicsigns of pulmonary hypertension nor electrocardio-graphic features of right ventricular overload. Lungperfusion scan was negative in three patients and notdone in patient 4. Three patients had elevated thyroidautoantibodies. Mean fT4 before therapy was62,4 6 42,5 pmol L21 and 11.3 6 3,3 pmol L21 aftertherapy. PAPs decreased from 40 6 11 mmHg beforeto 25 6 6 mmHg after therapy of hyperthyroidism.

Case reports

Case 1

A 25-year-old woman was treated for thyrotoxicosisdue to Graves disease for 2 years when she was 15years old. No further treatment or controls weredone. Three weeks before entry, the patient sufferedfrom nervousness, inability to sleep, tremors, exces-sive sweating and heat intolerance. Besides this, she

Table 1 Patient characteristics, therapy and outcome

PAPs before/after Pulse rate fT4 fT4therapy [mmHg] before/ before after

Case no. Thyroidal Elevated time interval after therapy therapysex, age disease antibodies [months] Therapy therapy [pmol/L] [pmol/L]

1, f, 26 Graves disease TSI, antimicrosomal 35/21, 6 thiamazoler iodine- 110/104 24.6 6antibodies 131

2, f, 79 Toxic multinodular none 34/26, 2 iodine-131 96/89 26.6 15goiter

3, f, 54 Graves disease antimicrosomal 56/35, 1 propyl-thiouracil 98/68 71.6 7.7antibodies

4, m, 24 Graves disease TSI 33/21, 12 thiamazole 72/53 99.2 11.2

TSI, thyroid-stimulatory immunoglobulin (reference range 010% inhibition); anti-microsomal antibodies (reference range 0350 IE mL21);fT4 free T4 hormone (reference range 8.519 pmol L21).

CASE REPORT: HYPERTHYROIDISM AND HYPERTENSION 187


remarked a swelling in the thyroidal region andhoarseness. On clinical examination, bilateral exoph-thalmus, tremor and hyperreflexia were noticed.Laboratory examinations revealed a TSH value below0.05 mU L21, and fT4 of 172 pmol L21.Antithyreoglobulin antibodies were within the nor-mal range, antimicrosomal antibodies were elevatedto 952 IE mL21, TSI was elevated to 49%. Because ofa slight cardiomegaly on chest radiograph, anechocardiography was performed. PAPs was35 mmHg. The left ventricle was normal with a nor-mal ejection fraction. A lung perfusion scan, arterialblood gas analysis and lung function tests were nor-mal.

The patient was treated with thiamazole and pro-pranolol initially. Two months later, radioiodine wasgiven. Weight gain and improvement of thyrotoxicsymptoms were remarked. Six months after fT4 wasnormalized, another echocardiogram showed adecrease from 35 to 21 mmHg in PAPs.

Case 2

A 79-year-old female patient suffered from weightloss, weakess and fatigue. Routine laboratory testsshowed suppressed TSH and elevated fT4.Antimicrosomal, antithyroglobulin antibodies, andthyroid-stimulating immunoglobulin were not ele-vated. The heart rate was normal. Radioiodine wasadministered after scintigraphic evidence of toxicmultinodular goiter. Because of the unsuspected ele-vation of pulmonary artery pressure in our firstpatient (case 1), an echocardiogram was performed.The PAPs was 34 mmHg. Left ventricular systolic anddiastolic function were normal. There was no scinti-graphic evidence of pulmonary embolism, and lungfunction tests were normal. The patient was treatedwith radioiodine with a consecutive normalization offT4. Two months later, a second echocardiographydocumented a decrease of PAPs to 26 mmHg.

Case 3

This 54-year-old woman presented with mild exoph-thalmus, weight loss and depression. Anti-microsomal antibodies were elevated, thyroid-stimulatory immunoglobulin was in the upper nor-mal limit and fT4 was elevated, so Graves diseasewas diagnosed. On routine chest radiograph car-diomegaly was documented. Signs of right heart fail-ure, dyspnea on exertion, ankle oedema and elevated

jugular vein pressure, were present. Pulmonary arte-rial hypertension was documented by Dopplerechocardiography. Pulmonary embolism was ruledout by a normal lung scintigram. Four weeks aftertherapy of the thyrotoxic state, exercise toleranceand signs of right heart failure recovered completelyand systolic pulmonary arterial pressure fell from 56to 35 mmHg.

Case 4

A 24-year-old man suffered from weight loss, palpita-tions, nervousness, sleep-disturbances and nauseaand was referred because of suspected hyperthy-roidism. Due to elevated fT4 and TSI-levels and a sup-pressed thyroid-stimulatory hormone (TSH), Gravesdisease was diagnosed. The chest radiograph wasnormal. An echocardiogram showed mild pul-monary hypertension (PAPs 33 mmHg) and a dilatedright atrium (diameter 4.5 cm). The patient wastreated with carbimazole and a beta-blocking agent.After six months, thyreostatic therapy was discontin-ued and TSH-levels remained normal. After another6 months, the echocardiogram was repeated, rightatrial diameter was 3.9 cm and PAPs decreased to21 mmHg.

Discussion

Herein, we report four cases with hyperthyroidismand coincidental pulmonary hypertension. At the in-patient and out-patient clinic of our referring univer-sity hospital with a population area of more than onemillion, we see about five cases of primary pul-monary hypertension every year. About 15 cases ofhyperthyroidism are newly diagnosed each year.

Our patients had no signs or symptoms of collagenvascular disease, liver disease, HIV infection, or histo-ry of anorectic substance use. At follow-up, allpatients are alive, in an euthyroid state and in goodhealth.

There is clear evidence for direct effects of thyroidhormones on the myocardium in addition to indirectones, e.g. by interaction with the sympathetic ner-vous system or alteration of the peripheral circula-tion and energy metabolism [9]. However, no dataabout invasively measured pulmonary haemody-namics in hyperthyroidism are available. Two patho-physiological mechanisms may explain the elevatedPAPs in our patients: an increase of cardiac output or

R. THURNHEER et al.188


an elevated pulmonary vascular resistance.Hyperthyroidism generally has only minor effects onmean arterial pressure because increases in systolicblood pressure, heart rate and circulating blood vol-ume are offset by decreases in diastolic blood pres-sure due to peripheral vasodilation [10]. Increasedcardiac output does not result in pulmonary hyper-tension in healthy subjects [11]. Thus, the pul-monary hypertension has to be attributed to anelevated pulmonary vascular resistance in ourpatients. An autoimmune pathogenetic link betweenPPH and thyroid diseases has been suggested [12].However, one of our patients (case 2) had no elevatedthyroid antibodies. Thus, another possible mecha-nism may be a direct influence of thyroid hormoneson the pulmonary vasculature. This is supported bythe regression of pulmonary hypertension after nor-malization of the hyperthyroid state. So far, PPHassociated with hyperthyroidism has been reportedin only two cases [13, 14].

In conclusion, these findings indicate an associa-tion between PPH and hyperthyroidism, which maybe clinically relevant. It is not yet determinedwhether PPH is due to hyperthyroidism itself, or if itrepresents a manifestation of the underlying autoim-mune disorder.

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Received 26 November 1996; accepted 1 April 1997.

Correspondence: Dr R. Thurnheer, Abteilung Pneumologie,Departement Innere Medizin Universittsspital, 8091 Zrich,Switzerland (fax: 10041 1 255 44 51).

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Hyperthyroidism and pulmonary hypertension