Occult Thyrotoxicosis: A Correctable Cause of “Idiopathic” Atrial Fibrillation

J. COLIN HUGH

FORFAR,

C. MILLER,

ANTHONY

MBChB, MBChB,

D. TOFT,

MD,

MRCP MRCP

MRCP

Edinburgh, Scotland

Serum total thyroxine, triiodothyronine and thyrotropin response to thyrotropin-releasing hormone were measured in 75 consecutive patients presenting to a cardiology clinic with atrial fibrillation with no obvious cardiovascular cause. A lack of response of serum thyrotropin to thyrotropin-releasing hormone, indicative of thyrotoxicosis, was found in 10 patients (13 percent), not all of whom had raised serum thyroid hormone levels. These 10 patients were predominantly male, had no clinical signs of thyrotoxicosls and a relative excess of nonpalpable autonomous thyroid nodules demonstrated with scintigraphy. Eight of the 10 patients had reversion to stable sinus rhythm after treatment with iodine-131 or carblmazole, either spontaneously or after direct current cardioversion. lt would appear that clinically occult thyrotoxicosis can be identified consistently only with the thyrotropin-releasing hormone test and is the cause of “ldiopathic” atrial fibrlllatlon in a significant proportion of patients.

Thyrotoxicosis has long been recognized as a major cause of atria1 fibrillation, accounting for 14 percent of cases in an early series.’ The original diagnostic tests for hyperthyroidism were relatively crude and in many instances the diagnosis was made primarily on clinical grounds. The advent of sophisticated tests of thyroid function has allowed a biochemical diagnosis to be made independent of clinical findings. This study was undertaken to identify the incidence of thyrotoxicosis in patients referred to a cardiology clinic for paroxysmal or persistent atria1 fibrillation in whom the diagnosis of thyrotoxicosis was not made by the referring practitioner or with confidence by the consulting cardiologist. Methods

From the Department of Cardiology, Royal Infirmary and University Department of Medicine, Edinburgh, Scotland. Manuscript received January 3, 1979; revised manuscript received February 13. 1979, accepted February 14, 1979. Address for reprints: J. Colin Forfar, MD, Department of Cardiology, The Royal Infirmary, Edinburgh EH3 9YW, Scotland.

Patients: Seventy-five consecutive patients (51 men and 24 women with a mean age of 58.6 f 12.4 [standard deviation] years) were studied. They were referred to the Department of Cardiology between August 1977 and November 1978 with sustained atria1 fibrillation that could not be satisfactorily explained on the basis of cardiovascular disease. In each case the atria1 fibrillation was confirmed with a routine electrocardiogram or ambulatory outpatient electrocardiographic monitoring. The atria1 fibrillation was considered “idiopathic” in 52 patients and an unexpected development in the natural history of an established cardiac disease in 23 patients (Table I). Mitral stenosis was excluded, where appropriate, with M mode echocardiography. A clinical diagnosis of thyrotoxicosis was suspected in two patients who each had slight diffuse enlargement of the thyroid gland. Biochemical measurements of thyroid function: In each of the 75 patients blood was withdrawn for the estimation of serum total thyroxine (TJ, triiodothyronine (Ts) and thyrotropin (TSH) level before and 20 minutes after the intravenous administration of 200 pg of thyrotropin-releasing hormone (TRH). Serum total triiodothyronine and thyroxine were measured with specific radioimmunoassays2; the interassay precision level using anonymous control sera

July 1979

The American Journal of CARDIOLOGY

Volume 44

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THYROTOXIC

ATRIAL FBRILLATION-FORFAR

ET AL.

averaged 7.9 percent for triiodothyronine and 11.7 percent for thyroxine, expressed as coefficient of variation. The normal ranges for serum total triiodothyronine were 1.1 to 2.2 nanomoles (nmol)/liter for men and 1.1 to 2.6 nmol/liter for women; those for serum total thyroxine were 60 to 150 nmol/liter for both sexes. Serum thyrotropin was also measured by radioimmunoassay in which the between assay coefficient of variation was 11.2 percent.” The normal range for serum thyrotropin was less than 0.7 to 5.7 mu/liter; and the normal range of response 20 minutes after the intravenous administration of 200 pg of thyrotropin-releasing hormone was 3.9 to 25.3 mU/liter.4 Diagnosis of thyrotoxicosis: For the purposes of this study the diagnosis of thyrotoxicosis was made not on clinical grounds but on the basis of lack of a serum thyrotropin response to thyrotropin-releasing hormone with or without raised levels of serum total triiodothyronine and thyroxine. Lack of response was defined as a failure of the 20 minute level of thyrotropin-releasing hormone to increase by more than 0.5 mu/liter above the basal level. A thyroid scan was performed using technetium-99m pertechnetate in 9 of the 10 patients with thyrotoxicosis.

Results An absent serum thyrotropin response to thyrotropin-releasing hormone was found in 10 (4 women, 6 men) of the 75 patients (13 percent), including 2 with associated heart disease in the form of an aortic and mitral valve lesion, respectively (Table I). The age, sex, levels of serum total triiodothyronine and thyroxine, the serum thyrotropin response to thyrotropin-releasing hormone, the thyroid scan appearances, the treatment and the cardiac rhythm after antithyroid therapy in these patients are shown in Table II. Except in Cases 2 and 8 the thyroid hormone levels in the serum were either normal or only modestly elevated. The highest serum total thyroxine level was recorded in Patient 8, whose dominant clinical feature was extreme apathy. In 8 of the 10 patients stable sinus rhythm returned after antithyroid treatment, spontaneously in 6 and after cardioversion in 2.

TABLE I Possible Cardiovascular Causes of Atrial Fibrillation in 23 of the 75 Patients Studied Patients (no.) Diagnosis lschemic heart disease Suspected angina of effort or previous myocardial infarction Hypertension Congenital heart disease Persistent ductus arteriosus Divided ductus arteriosus Mild pulmonary valve stenosis Aortic valve prosthesis Rheumatic heart disease Trivial mitral stenosis Mild aortic regurgitation Other Mild mitral regurgitation Alcoholic cardiomyopathy Total l

10

Male

Female

7

3

1

1

: I.:* 1 1 1’

The American Journal of CARDIOLOGY

The two patients (Cases 1 and 10) with normal levels of serum total triiodothyronine and thyroxine merit further description. Case 1: A 46 year old woman was referred from another hospital because of an uncontrolled ventricular rate associated with dyspnea on exertion. Tachycardia persisted despite therapeutic serum digoxin levels and administration of oral propranolol, 10 mg every 8 hours. There were no clinical or historical features of thyrotoxicosis and no clinical, radiographic or echocardiographic evidence of mitral valve disease. Serum total thyroxine levels were repeatedly normal as were the serum total triiodothyronine levels, estimated for the first time after the administration of propranolol. Several attempts at direct current cardioversion at a maximum of 400 joules failed to establish a sinus rhythm. Because of the lack of serum thyrotropin response to thyrotropin-releasing hormone and the presence of a nonpalpable autonomous thyroid nodule detected with scintigraphy, a therapeutic dose of iodine-131 was administered. Nine months later direct current cardioversion was successful at 100 joules. Serum total thyroxine had decreased from 102 to 80 nmol/liter and serum total triiodothyronine from 2.4 to 1.6 nmol/liter, and the serum thyrotropin response to thyrotropin-releasing hormone was normal. It was assumed that the patient had a triiodothyronine thyrotoxicosis associated with an autonomous thyroid nodule but that the serum total triiodothyronine level was lowered by the administration of propranolol. Case 10: A 67 year old woman had severe heart failure and bilateral pleural effusions associated with atria1 fibrillation and an uncontrolled ventricular rate. The ventricular rate and the heart failure responded to treatment with bed rest and administration of digoxin and diuretic agents. Because of the lack of serum thyrotropin response to thyrotropin-releasing hormone, carbimazole was added to the therapeutic regimen. The atria1 fibrillation reverted to stable sinus rhythm 6 weeks later, when the serum total triiodothyronine level had fallen from 1.8 to 1.2 nmol/liter and the serum total thyroxine level from 125 to 90 nmol/liter. The serum thyrotropin response to thyrotropin-releasing hormone was normal. It was thought that this patient, too, had a triiodothyronine form of thyrotoxicosis and that the severity of the heart failure resulted in a lowering of the serum total triiodothyronine level. The low levels of thyroid hormones in these two cases could not be accounted for by a reduced concentration of thyroid hormone-binding proteins because in each case the free thyroxine index was normal.

No patient presenting to the cardiology clinic with atrial fibrillation was considered to have thyrotoxicosis by the referring medical practitioner. Furthermore, only 2 of the 10 patients ultimately found to have thyrotoxicosis on the basis of biochemical criteria were suspected of having the disease by the consulting cardiologist. The rate of clinical detection of thyrotoxicosis might have been higher if the patients had been examined by an endocrinologist rather than a cardiologist. However, the typical signs and symptoms of thyrotoxicosis may be

9

Patients with thyrotoxicosis.

July 1979

Illustrative Cases

Discussion

1

1:

In each of the remaining 65 patients there was a normal serum total triiodothyronine, thyroxine and thyrotropin response to thyrotropin-releasing hormone.

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absent in the older patient and the course of the disease may be dominated by heart failure and gastrointestinal or cerebral symptoms.5 In some elderly patients with thyrotoxicosis, illustrated by Case 8, the major features are those of extreme apathy and weight 10ss.~+~ Screening tests for hyperthyroidism: Measurement of a single thyroid hormone is not a sufficient screening test for thyrotoxicosis in patients with atria1 fibrillation. If the measurement of serum total thyroxine were the only thyroid function test employed in patients with atria1 fibrillation due to “triiodothyronine-toxicosis” the condition would remain undetected. Indeed our study revealed an unexpected proportion of thyrotoxic patients with hyperfunctioning solitary thyroid nodules, and it is well recognized that there is a large incidence of preferential hypersecretion of triiodothyronine by such “hot” nodules.8 Measurement of serum total triiodothyronine levels would be equally unsatisfactory as a screening test. Most circulating total triiodothyronine is derived from the peripheral monodeiodination of thyroxine. However, an alternative peripheral monodeiodination of thyroxine to form metabolically inactive reverse triiodothyronine predominates in nonthyroidal illness9 or as a result of drug therapy with propranolollcJ1 or corticosteroids.‘2 Thyrotoxic patients with associated nonthyroidal illness such as heart failure (Case 10) or those receiving drugs such as propranolol (Case 1) or corticosteroids may have serum total triiodothyronine levels within the normal range.1:3,14 Furthermore serum total triiodothyronine levels are lowered with increasing age in healthy subjects over age 65 years,15 but reference normal ranges cited by laboratories are usually based on levels found in healthy young adults. In all forms of thyrotoxicosis there is a lack of response to serum thy-

ATRIAL FIBRILLATION-FORFAR

ET AL.

rotropin after the administration of thyrotropin-releasing hormone, and this response is unaffected by the previously described factors influencing serum total triiodothyronine levels. The thyrotropin-producing cells of the anterior pituitary gland, the thyrotropes, are very sensitive to changes in circulating thyroid hormone levels within the normal range, and a lack of response of serum thyrotropin to thyrotropin-releasing hormone may occur in a euthyroid patient whose serum total triiodothyronine and thyroxine levels are elevated for that person but still within the accepted normal range.16 It could be argued that Patients 1 and 10, whose serum total triiodothyronine and thyroxine levels were within their respective normal ranges, did not have thyrotoxic atria1 fibrillation. However, stable sinus rhythm was established in both patients after antithyroid treatment. Causes of atria1 fibrillation: Atria1 fibrillation occurs in 10 percent of patients with clinically overt thyrotoxicosis,17 but it is not clear why the arrhythmia should develop in older patients with minor increases in circulating triiodothyronine and thyroxine levels or occur more commonly in men than in women. It is possible that these patients have coexistent subclinical ischemic heart disease or that there is simply a marked patient to patient variation in the sensitivity of the myocardium to thyroid hormones. Role of anticoagulant therapy: Although the use of long-term anticoagulant agents in patients with rheumatic heart disease complicated by atria1 fibrillation is widely accepted, is it has not been our policy to give anticoagulant therapy to patients with thyrotoxic atria1 fibrillation. However, Staffurth et al.19 recently suggested that the prophylactic use of anticoagulant agents in this latter group of patients can reduce the

TABLE II Age, Sex, Serum Total Triiodothyronine (T3) and Thyroxine (Tp) Levels, Thyrotropin-Releasing Hormone (TRH) Test, Thyroid Scan Results, Treatment and Eventual Cardiac Rhythm in the 10 Patients With Thyrotoxicosis Serum Serum Total T4 Total Ts (nmol/liter) (nmol/liter)

Serum TSH (mU/liter) Response to TRH 20 min Basal

Thyroid Scan

Case no.

Age (yr) & Sex

1

46F

2.4

102

1.5

1.3

2

58F

5.4

242

1.1

1.2

3

51M

3.0

127

0.9

1.2

4

51M

4.5

188

1.7

2.0

5

73M

4.3

193

1.2

1.0

6

76M

2.8

162

1.0

7

47M

4.1

190

Occult thyrotoxicosis: a correctable cause of "idiopathic" atrial fibrillation.

Occult Thyrotoxicosis: A Correctable Cause of “Idiopathic” Atrial Fibrillation J. COLIN HUGH FORFAR, C. MILLER, ANTHONY MBChB, MBChB, D. TOFT,...
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