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Departments of Endocrinology (J.A.S., H.E.V.) and Internal Medicine (F.G.V., B.G.), Marilia Medical School and Department of Endocrinology, Faculdade Ciências Médicas Pontifícia Universidade Católica de Campinas (J.H.R.), São Paulo, Brazil 04029-000
Address all correspondence and requests for reprints to: Prof. João Hamilton Romaldini, Avenida Indianopólis, 530. CEP 04062-000, São Paulo, Brazil. E-mail: jhroma{at}netpoint.com.br.
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Abstract |
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Introduction |
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Cardiovascular abnormalities have been reported in some studies (13, 14, 15, 16, 17), but not in all (18). The alterations described are similar to the ones found in overt hyperthyroidism, but most of these studies are related to exogenous subclinical hyperthyroidism by the use of TSH-suppressive doses of T4. For clinical purposes, the most important problem is to define whether patients with spontaneous subclinical hyperthyroidism should be treated or not; however, there is a paucity of studies that have been made to investigate this clinical dilemma (19, 20, 21).
To evaluate the potential cardiac benefits of an early antithyroid treatment, we designed a detailed clinical and cardiological study in patients with endogenous subclinical hyperthyroidism. The results showed that some cardiac disturbances underwent reversibility after restoring the euthyroid state.
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Subjects and Methods |
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The study included 10 consecutive newly diagnosed patients with endogenous subclinical hyperthyroidism before and 6 months after reaching euthyroidism with methimazole (MMI) treatment, selected from the Endocrine Clinic at the Marília Medical School (São Paulo, Brazil). The diagnosis was based on the finding of low serum TSH values (<0.1 mU/liter) and free T4 (FT4) and free T3 (FT3) concentrations within the normal range, maintained stable for at least 90 d, and confirmed by the association with a suppressed response of TSH to a TRH test.
The clinical and laboratory characteristics of the patients are shown in Table 1
. The presence of solitary or toxic multinodular goiter was confirmed by 131I-thyroid scan as well as the absence of serum antithyroglobulin, antithyroidperoxidase (TPOAb), and TSH-receptor (TRAb) antibodies. Graves’ disease was defined as those patients who presented diffuse goiters, homogeneous 131I-thyroid scan distribution and ophthalmopathy signs, or the presence of either positive serum TPOAb or TRAb. None of the patients, at the time of a physical examination, had a history or evidence of thyroid, cardiovascular, or respiratory diseases; diabetes; alcoholism; psychiatric diseases; nor were they using corticosteroid, amiodarone, or any medication that could affect cardiovascular or thyroid function tests. Patients with euthyroid sick syndrome were excluded from our study. The control group consisted of 10 volunteers matched for age, gender, and body mass index. They were in good general health, had no history of endocrine diseases, and were not taking any medications (Table 2).
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The ethics committees of the two participating centers approved the protocol, and all subjects signed informed consents.
Patients and controls were submitted to clinical and cardiac evaluation, including echocardiography and ambulatory electrocardiography 24-h monitoring (Holter). The initial dose of MMI was given according to the Wayne index test. The initial dose was 30 mg daily (patient 9, Table 1
) for the highest score. The MMI dose was 10 mg daily for the lowest score (patient 6, Table 1), and the dose was 20 mg of MMI daily for the remaining eight patients. The MMI dose was adjusted on the basis of serial thyroid function tests performed at 3-wk intervals. Patients were reevaluated 6 months after achieving a stabilized euthyroid state defined by the results of clinical findings, the Wayne clinical index less than 11, keeping the serum FT4 and TSH values in the normal range.
Clinical and hormonal data
Symptoms and signs of hyperthyroidism were evaluated by the Wayne clinical index (22). According to this test, a score of 19 or more is indicative of overt hyperthyroidism, a score of 11 or less is consistent with a euthyroid state, and a score between 11 and 19 is doubtful.
Serum TSH concentration was measured by a sensitive enzyme immunoassay (Ultrasensitive Human TSH II, Axsym System, Abbott Laboratories, Inc., Abbott Park, IL) that has a detection limit of 0.03 mU/liter and a functional sensitivity of 0.06 mU/liter. The interassay coefficients of variation were 9.8% at 0.06 mU/liter, 5.1% at 0.8 mU/liter, 3.7% at 7.5 mU/liter, and 3.0% at 25 mU/liter. The normal range of serum TSH in our laboratory was 0.32–5.2 mU/liter. Serum free thyroid hormone concentrations were measured by fluoroimmunoassay, using Delphia techniques (Pharmacia, Wallac Oy, Turku, Finland) with normal ranges of 10.3–24.5 pmol/liter for FT4 and 2.8–6.1 pmol/liter for FT3. Serum TPOAb was measured by a sensitive direct RIA (RSR Limited, Cardiff, UK), and the upper limit of reference was 0.3 IU/ml. Serum TRAb concentration was determined by a radioreceptor assay (RSR Limited, Cardiff, Wales, UK), and values above 10 U/liter were considered positive.
Cardiological evaluation
A standard 12-lead electrocardiography and Holter monitoring was performed on each patient and control to detect rhythm disturbance by using electrocardiography monitoring (Oxford Medical Ltd., Abingdon, Oxon, UK). The printed tapes were analyzed blindly by a single observer (B.G.).
Complete two-dimensional (2D) and Doppler echocardiographic studies were performed and interpreted by an observer (F.G.V.) who was unaware of the clinical data by using an ultrasound system (ATL Apogee, CX 250, Seattle, WA) equipped with a 2.25-mHz transducer and recorded on videotape. The measurements were obtained according to the recommendations described by the American Society of Echocardiography (23). Three measurements were averaged for each value from 10 consecutive cardiac cycles. M-mode echocardiography, 2D and 2D-directed pulsed-wave Doppler recordings were obtained by standard methods (23, 24), and measurement was made online with the Interspect Apogee measurement software package. The following measurements were obtained, and the results were given in centimeters: left ventricular internal dimension at diastole and systole, interventricular septum thickness at diastole, left ventricular posterior wall thickness at diastole, and left atrial diameter. Left ventricular mass index was calculated according to the Devereux and Reichek method (25).
Doppler flow signals were obtained by using the methods described by the Canadian Consensus Recommendations for the Measurement and Reporting of Diastolic Dysfunction Echocardiography (24) with the transducer positioned at the cardiac apex for all of the following measurements: early diastolic peak flow velocity (peak E), late diastolic peak flow velocity (peak A), their ratio (E/A), deceleration time, acceleration time of early filling, peak E deceleration rate, and isovolumetric relaxation time. We also measured five parameters of left ventricular functions: shortening fraction, ejection fraction, velocity of circumferential fiber shortening, cardiac index, and end-systolic wall stress.
Statistical analysis
Statistical analysis was performed by using the Mann-Whitney U test to evaluate differences between the groups. For comparisons between the patients before and after treatment, we used the Wilcoxon signed rank test. Correlation between serum TSH, free thyroid hormone concentrations, and both clinical and cardiological data were determined by the Spearman correlation coefficient test. Data were expressed as the median and range, and a two-tailed P value less than 0.05 was considered significant. The computer program GB-STAT professional version 6.5 (Dynamic Microsystems Inc., Buccaneer Road, Silver Spring, MD) was used to analyze the data.
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Results |
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The MMI maintenance dose was 12.5 mg daily (range, 5–30 mg), and the whole period of treatment was 9.1 months (range, 7–13 months).
The Wayne clinical index was significantly greater in subclinical hyperthyroidism patients than controls, both before (P = 0.001) and after (P = 0.05) MMI therapy (Table 2). Furthermore, there was a significant reduction in the Wayne clinical index after reaching the euthyroid state (P = 0.004). The main clinical manifestations observed were palpitations, tiredness, excessive sweating, nervousness, weakness, and preference for cold. The Wayne clinical index was significantly correlated with serum TSH (rs = -0.5; P = 0.004) but not with FT4 and FT3 values.
Thyroid function tests
Serum TSH concentrations were suppressed in all patients before treatment and returned to normal values 2.5 months (range, 1–7 months) after MMI therapy. Serum FT4 levels were within the normal range, but they were higher in the subclinical hyperthyroid group at baseline than in controls (P = 0.002), and they decreased after reaching the euthyroid state (P = 0.002). There was no difference between patients after treatment and the controls. Serum FT3 concentrations did not differ among the groups (Table 2).
Cardiological data
The standard electrocardiography was considered normal in all patients and controls. The Holter data are summarized in Table 3 and show some significant alterations in the patients compared with controls. After reaching the euthyroid state, subclinical hyperthyroid patients presented a significant reduction in heart rate (P = 0.008), total number of beats during 24 h (P = 0.004), number of atrial premature beats (P = 0.002), and ventricular premature beats (P = 0.003). A significant correlation was found between serum TSH and FT4 levels to both atrial premature beats (rs = -0.6, P = 0.0003; and rs = 0.5, P = 0.004, respectively) and ventricular premature beats (rs = -0.56, P = 0.001; and rs = 0.36, P = 0.04, respectively). The mean heart rate correlated only with serum FT4 values (rs = 0.4; P = 0.01).
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. In the left ventricular dimensions, we observed an increase in the interventricular septum thickness (P = 0.02), left ventricular posterior wall thickness (P = 0.05), and left ventricular mass index (P = 0.02) in patients with subclinical hyperthyroidism compared with controls. After reaching the euthyroidism, these measurements were similar to the controls (Table 4 and Fig. 1). Interventricular septum thickness decreased in 8 patients, left ventricular posterior wall thickness in 9, and left ventricular mass index in 7 of the 10 patients after MMI therapy. Left ventricular hypertrophy was not observed in any patient, and other left ventricular dimensions were not different among the groups.
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4). Regarding the systolic function, we did not observe any difference among the groups.
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Discussion |
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In the present study, our patients presented clinical manifestations similar to those observed in overt hyperthyroidism. The high Wayne clinical index obtained in the patients was in a range in which the clinical diagnosis could be considered doubtful. Nevertheless, the symptoms significantly improved or disappeared after reaching the euthyroid state, establishing an association among the symptoms and a mild thyrotoxic state. Similar findings were found in other studies, but the patients were not submitted to a specific antithyroid treatment. Stott et al. (33) observed that elderly patients with subclinical hyperthyroidism had mild symptoms on the Wayne clinical index that differed from those of euthyroid controls. Furthermore, Biondi et al. (17) found a significant prevalence of thyrotoxic symptoms in young and middle-aged patients with endogenous subclinical hyperthyroidism. Taken together with the results of the present study, these data demonstrate that subclinical hyperthyroidism is a symptomatic condition and can affect the quality of life.
Subclinical hyperthyroidism has been associated with several heart effects (13, 16, 34), but the main cardiovascular morbidity is the atrial fibrillation (35). In the Framingham population, the relative risk of atrial fibrillation in elderly subjects with low serum TSH levels as compared with those with normal TSH concentrations was 3.1 (14). These results indicate that subclinical hyperthyroidism is related to a higher cardiovascular risk in older patients and raised the question of whether these patients should receive early treatment to prevent atrial fibrillation. This dilemma is of great clinical importance because the risk of arterial thromboembolism is increased in patients with thyrotoxicosis and atrial fibrillation (36, 37). Furthermore, a single measurement of low serum TSH in individuals aged 60 yr or older was recently associated with increased mortality, in particular due to circulatory and cardiovascular diseases (30).
In the present study, our patients presented a significant increase in the mean heart rate, total number of beats during 24 h, and atrial and ventricular premature beats. Furthermore, TSH and FT4 correlated significantly with atrial and ventricular premature beats, indicating an influence of thyroid function on cardiac-rhythm disturbances. Six months after reaching the euthyroidism, these heart rhythm abnormalities significantly improved or disappeared, suggesting that an earlier antithyroid therapy might avoid the potential progression to more complex arrhythmias. We did not observe atrial fibrillation in these patients because of their age (not so old) or the prevalence of supraventricular arrhythmia, reported to be higher in patients with exogenous subclinical hyperthyroidism than in patients with endogenous subclinical hyperthyroidism (17). The mechanism by which thyroid hormone induces rhythm disturbances is probably related in part to direct chronotropic effects and in part to indirect effects on the sympathoadrenergic system (5). These possibilities are supported by the present study using specific antithyroid therapy and by others using ß-adrenergic blockade (38).
In this study, heart morphology was also compromised. The patients with subclinical hyperthyroidism presented a mild increase in left ventricular mass index, reflected by increased interventricular septum thickness and left ventricular posterior wall thickness at diastole, but it was not sufficient to cause left ventricular hypertrophy. These results are in accordance with Shapiro et al. (18). A significant reduction in the heart size was observed 6 months after stable normalization of serum TSH concentration, indicating that this slight increase in the cardiac mass could probably progress to hypertrophy and that an early treatment might avoid the progression of the disease. Thyroid hormone excess may provoke left ventricular hypertrophy by combined direct transcriptional (4) and indirect nontranscriptional effects by increasing peripheral oxygen consumption, cardiac contractility, and the cardiac work (39). The increased heart rate could explain the mild increase in heart size observed in our patients. Ching et al. (40) also described a mild increase in left ventricular mass index in the absence of marked alterations in heart rate and systolic function in patients with exogenous hyperthyroidism. Mercuro et al. (16) reported a significant decrease in left ventricular mass index after a careful adjustment of the T4 dose, pointing out a direct action of thyroid hormone on the heart. In contrast, Biondi et al. (38) observed a reduction in left ventricular mass index after a period of treatment with bisoprolol (38), indicating an indirect effect of thyroid hormone on the heart morphology. Thus, it seems that a direct and indirect mechanism could be involved in the pathogenesis of left ventricular hypertrophy associated to subclinical hyperthyroidism. However, in this condition the basal serum free thyroid hormone levels are within the normal range, suggesting that the clinical abnormalities might be explained by thyroid hormone levels above the hypothalamic-pituitary set point for the patient either by increased thyroid hormone concentrations in organ tissues or by possible fluctuations in thyroid hormone secretion.
In patients with overt hyperthyroidism, there is an enhanced cardiac diastolic performance (41). Our data showed that subclinical hyperthyroidism slightly affected diastolic function, but no alteration was found after reaching euthyroidism. An impairment of diastolic function has been observed (34), and it could be explained by the offsetting effect of left ventricular hypertrophy in detriment of the beneficial effects of thyroid hormone over diastolic function (4).
The findings of the present study and others show that there is now clear evidence that subclinical hyperthyroidism is not just a laboratory condition and it can cause several morbidities (14, 27, 28, 29, 30), affect quality of life (17), and increase mortality from all causes (30). Although this is one of the first studies to evaluate the effects of early antithyroid treatment for endogenous subclinical hyperthyroidism and despite having some limitations, such as the small number of patients and nonrandomized design, we believe that our findings highlight that the euthyroid state was related to an improvement of the clinical, laboratory, and cardiac disturbances. It suggests that early antithyroid therapy should be considered in patients with endogenous subclinical hyperthyroidism where it is needed to prevent potential progression to a more advanced heart disease.
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Footnotes |
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Abbreviations: 2D, Two-dimensional; E/A, early to late diastolic peak flow velocity ratio; FT3, free T3; FT4, free T4; MMI, methimazole; peak A, late diastolic peak flow velocity; peak E, early diastolic peak flow velocity; TPOAb, antithyroidperoxidase antibodies; TRAb, TSH-receptor antibodies.
Received July 8, 2002.
Accepted January 16, 2003.
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