0013-7227/03/$15.

00/0 The Journal of Clinical Endocrinology & Metabolism 88(4):16721677

Printed in U.S.A. Copyright 2003 by The Endocrine Society
doi: 10.1210/jc.2002-021046

The Effects of Early Antithyroid Therapy for

Endogenous Subclinical Hyperthyroidism in
Clinical and Heart Abnormalities
JOSE A. SGARBI, FABIO G. VILLACA, BENITO GARBELINE, HELOISA E. VILLAR, AND
JOAO H. ROMALDINI
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 Ciencias Medicas Pontifcia Universidade Catolica de Campinas (J.H.R.), Sao
Paulo, Brazil 04029-000

Subclinical hyperthyroidism has been associated with harm- (P 0.009), interventricular septum thickness (P 0.008), and
ful cardiac effects, but its treatment remains controversial. left ventricular posterior wall thickness (P 0.004) at diastole.
This study was designed to assess the cardiac effects of the Furthermore, the early diastolic peak flow velocity deceler-
normalization of serum TSH concentration in patients with ation rate was significantly higher (P 0.02) in the untreated
endogenous subclinical hyperthyroidism. Ten patients (me- patients compared with controls. The Wayne clinical index
dian age, 59 yr; range, 16 72 yr) with normal serum free T4 and was higher in patients than in controls (P 0.001) and de-
free T3 concentration and a stable suppression of serum TSH creased after treatment (P 0.004). Serum TSH concentration
levels were evaluated by Doppler-echocardiography, by stan- returned to normal values after 2.5 months (range, 1.0 7.0
dard and 24-h electrocardiography monitoring (Holter), and months) on methimazole therapy (0.05 vs. 1.42 mU/liter; P
by the clinical Wayne index. Ten subjects, matched for age and 0.002). Serum free T4 values were normal in patients before
sex, were used as controls. Patients were reevaluated 6 treatment but significantly decreased after reaching the eu-
months after achieving stabilized euthyroidism by using me- thyroidism (16.9 vs. 11.5 pmol/liter; P 0.002). In contrast,
thimazole with a median initial dose of 20 mg daily (10 30 mg serum free T3 concentration did not differ among the groups.
daily). After reaching euthyroidism, we found a significant In conclusion, our findings support that early antithyroid
decrease in the heart rate (P 0.008), the total number of beats therapy should be considered in patients with endogenous
during 24 h (P 0.004), and the number of atrial (P 0.002) and subclinical hyperthyroidism, where it is needed to prevent
ventricular (P 0.003) premature beats. Echocardiographical potential progression to a more advanced heart disease.
data resulted in a reduction of the left ventricular mass index (J Clin Endocrinol Metab 88: 16721677, 2003)

T HE IMPLICATIONS OF overt hyperthyroidism on ones

general health are well known (1), particularly the in-
volvement of the cardiovascular system (25). In contrast, the
diological study in patients with endogenous subclinical hy-
perthyroidism. The results showed that some cardiac
disturbances underwent reversibility after restoring the eu-
consequences to ones health in subclinical hyperthyroidism, thyroid state.
a condition defined by low or undetectable serum TSH con-
centration and normal free thyroid hormone levels (6), are Subjects and Methods
not well established (7), and the need for a specific treatment
Subjects
is still controversial (8 12).
Cardiovascular abnormalities have been reported in some The study included 10 consecutive newly diagnosed patients with
endogenous subclinical hyperthyroidism before and 6 months after
studies (1317), but not in all (18). The alterations described reaching euthyroidism with methimazole (MMI) treatment, selected
are similar to the ones found in overt hyperthyroidism, but from the Endocrine Clinic at the Marlia Medical School (Sao Paulo,
most of these studies are related to exogenous subclinical Brazil). The diagnosis was based on the finding of low serum TSH values
hyperthyroidism by the use of TSH-suppressive doses of T4. (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
For clinical purposes, the most important problem is to de- the association with a suppressed response of TSH to a TRH test.
fine whether patients with spontaneous subclinical hyper- The clinical and laboratory characteristics of the patients are shown
thyroidism should be treated or not; however, there is a in Table 1. The presence of solitary or toxic multinodular goiter was
paucity of studies that have been made to investigate this confirmed by 131I-thyroid scan as well as the absence of serum antithy-
roglobulin, antithyroidperoxidase (TPOAb), and TSH-receptor (TRAb)
clinical dilemma (19 21). antibodies. Graves disease was defined as those patients who presented
To evaluate the potential cardiac benefits of an early an- diffuse goiters, homogeneous 131I-thyroid scan distribution and oph-
tithyroid treatment, we designed a detailed clinical and car- thalmopathy 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;
Abbreviations: 2D, Two-dimensional; E/A, early to late diastolic peak diabetes; alcoholism; psychiatric diseases; nor were they using cortico-
flow velocity ratio; FT3, free T3; FT4, free T4; MMI, methimazole; peak steroid, amiodarone, or any medication that could affect cardiovascular
A, late diastolic peak flow velocity; peak E, early diastolic peak flow or thyroid function tests. Patients with euthyroid sick syndrome were
velocity; TPOAb, antithyroidperoxidase antibodies; TRAb, TSH-recep- excluded from our study. The control group consisted of 10 volunteers
tor antibodies. matched for age, gender, and body mass index. They were in good

1672

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Sgarbi et al. Subclinical Hyperthyroidism and Cardiac Effects J Clin Endocrinol Metab, April 2003, 88(4):16721677 1673

TABLE 1. Clinical and laboratory characteristics in patients with persistent endogenous subclinical hyperthyroidism

Wayne
Age TSH FT4 FT3 TRAb TPOAb
No. clinical Thyroid goiter Comment
(yr)/sex (mU/liter) (pmol/liter) (pmol/liter) (U/liter) (IU/ml)
index
1 16/F 13 0.05 13.3 5.9 11 0.3 Solitary nodule
2 52/F 17 0.05 17.8 4.7 11 0.3 Multinodular
3 61/F 4 0.05 18.9 2.8 11 13.7 Diffuse
4 69/F 10 0.05 15.1 4.7 11 0.3 Multinodular Adenomatous goiter
5 72/M 14 0.05 15.9 3.5 11 0.3 Diffuse Signs of ophthalmopathy
6 41/F 0 0.05 13.4 3.8 11 0.3 Multinodular Adenomatous goiter
7 57/F 16 0.05 20.6 5.0 11 0.3 Multinodular
8 56/F 11 0.07 15.4 4.0 11 0.3 Multinodular
9 66/F 19 0.05 20.6 4.5 11 0.3 Solitary nodule
10 62/F 7 0.05 17.8 3.4 11 24.3 Diffuse Signs of ophthalmopathy
M, Male; F, female.

TABLE 2. Clinical and laboratory characteristics of controls and subclinical hyperthyroidism (SCH) patients before and 6 months after
achieving stabilized euthyroidism by antithyroid treatment

SCH patients before therapy SCH patients after therapyd

Controls (n 10) Pa Pb Pc
(n 10) (n 10)
Age (yr) 52.0 (16 66) 0.25 59.0 (16 72) 0.9 59.3 (16 73) 0.22
Gender (F/M) 9/1 9/1 9/1
Body mass index (kg/m2) 28.2 (18.132.0) 0.83 28.5 (16.6 33.6) 0.64 29.5 (16.6 32.8) 0.4
Wayne clinical index 1.0 (7.0 7.0) 0.001 12.0 (0.0 19.0) 0.004 2.0 (0.0 11.0) 0.03
TSH (mU/liter) 1.5 (0.53 4.2) 0.0001 0.05 (0.05 0.07) 0.002 1.42 (0.433.5) 0.43
FT4 (pmol/liter) 12.9 (10.314.8) 0.002 16.9 (13.320.6) 0.002 11.5 (7.716.8) 0.39
FT3 (pmol/liter) 3.55 (2.75.6) 0.3 4.25 (2.8 5.9) 0.16 3.75 (2.1 4.5) 0.73
Results are expressed as median (range). P 0.05 was considered significant. F, Female; M, male.
a
Controls vs. SCH patients before treatment by the Mann-Whitney U test.
b
SCH patients before vs. after treatment by Wilcoxon signed-rank test.
c
SCH patients after treatment vs. controls by the Mann-Whitney U test.
d
Six months after reaching the euthyroidism.

general health, had no history of endocrine diseases, and were not taking
any medications (Table 2).
Study design
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 evalu-
ation, 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 im-
munoassay (Ultrasensitive Human TSH II, Axsym System, Abbott Lab-
oratories, 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 0.325.2 mU/liter. Serum free thyroid hormone
concentrations were measured by fluoroimmunoassay, using Delphia
techniques (Pharmacia, Wallac Oy, Turku, Finland) with normal ranges
of 10.324.5 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 Echocar-
diography (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 mea-
surements: 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 relax-
ation time. We also measured five parameters of left ventricular func-
tions: shortening fraction, ejection fraction, velocity of circumferential
fiber shortening, cardiac index, and end-systolic wall stress.

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1674 J Clin Endocrinol Metab, April 2003, 88(4):16721677 Sgarbi et al. Subclinical Hyperthyroidism and Cardiac Effects

Statistical analysis state, subclinical hyperthyroid patients presented a signifi-

Statistical analysis was performed by using the Mann-Whitney U test cant reduction in heart rate (P 0.008), total number of beats
to evaluate differences between the groups. For comparisons between during 24 h (P 0.004), number of atrial premature beats
the patients before and after treatment, we used the Wilcoxon signed (P 0.002), and ventricular premature beats (P 0.003). A
rank test. Correlation between serum TSH, free thyroid hormone con- significant correlation was found between serum TSH and
centrations, and both clinical and cardiological data were determined by
the Spearman correlation coefficient test. Data were expressed as the
FT4 levels to both atrial premature beats (rs 0.6, P
median and range, and a two-tailed P value less than 0.05 was consid- 0.0003; and rs 0.5, P 0.004, respectively) and ventricular
ered significant. The computer program GB-STAT professional version premature beats (rs 0.56, P 0.001; and rs 0.36, P
6.5 (Dynamic Microsystems Inc., Buccaneer Road, Silver Spring, MD) 0.04, respectively). The mean heart rate correlated only with
was used to analyze the data. serum FT4 values (rs 0.4; P 0.01).
Echocardiography data are detailed in Table 4. In the left
Results
ventricular dimensions, we observed an increase in the in-
Clinical data terventricular septum thickness (P 0.02), left ventricular
The MMI maintenance dose was 12.5 mg daily (range, 530 posterior wall thickness (P 0.05), and left ventricular mass
mg), and the whole period of treatment was 9.1 months index (P 0.02) in patients with subclinical hyperthyroidism
(range, 713 months). compared with controls. After reaching the euthyroidism,
The Wayne clinical index was significantly greater in sub- these measurements were similar to the controls (Table 4 and
clinical hyperthyroidism patients than controls, both before Fig. 1). Interventricular septum thickness decreased in 8 pa-
(P 0.001) and after (P 0.05) MMI therapy (Table 2). tients, left ventricular posterior wall thickness in 9, and left
Furthermore, there was a significant reduction in the Wayne ventricular mass index in 7 of the 10 patients after MMI
clinical index after reaching the euthyroid state (P 0.004). therapy. Left ventricular hypertrophy was not observed in
The main clinical manifestations observed were palpitations, any patient, and other left ventricular dimensions were not
tiredness, excessive sweating, nervousness, weakness, and different among the groups.
preference for cold. The Wayne clinical index was signifi- In relation to diastolic function, peak E, peak A, and the
cantly correlated with serum TSH (rs 0.5; P 0.004) but E/A ratio were not different in the three groups. Compared
not with FT4 and FT3 values. with controls, peak E deceleration rate was significantly
higher in subclinical hyperthyroid patients before treatment
Thyroid function tests (P 0.02), but no difference occurred after the euthyroid
state. Furthermore, there was a tendency to a faster decel-
Serum TSH concentrations were suppressed in all patients
eration time (P 0.05) in patients compared with control
before treatment and returned to normal values 2.5 months
subjects (Table 4).
(range, 17 months) after MMI therapy. Serum FT4 levels
Regarding the systolic function, we did not observe any
were within the normal range, but they were higher in the
difference among the groups.
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 Discussion
after treatment and the controls. Serum FT3 concentrations Since the introduction of sensitive TSH assay generations
did not differ among the groups (Table 2). (26) there has been a continuous debate about subclinical
hyperthyroidism and its clinical implications. This is truly an
Cardiological data
exciting moment because new efforts have been made to
The standard electrocardiography was considered normal clarify some controversial issues as to whether subclinical
in all patients and controls. The Holter data are summarized hyperthyroidism could be related to systemic effects and
in Table 3 and show some significant alterations in the pa- whether it should be treated or not. Some studies have dem-
tients compared with controls. After reaching the euthyroid onstrated new evidence about organ involvement (1316,

TABLE 3. Electrocardiography 24-h monitoring (Holter) in controls and in patients with subclinical hyperthyroidism (SCH), before and 6
months after achieving stabilized euthyroidism by antithyroid treatment

SCH before therapy SCH after therapyd

Controls (n 10) Pa Pb Pc
(n 10) (n 10)
Heart rate (beats/min) 73.5 (56 80) 0.04 81.5 (70 94) 0.008 73.5 (56 89) 0.73
Total 24-h heart rate 96,132 (74,929 109,251) 0.1 104,658 (76,449 134,806) 0.004 91,802 (68,437123,255) 0.79
(beats/24 h)
Atrial premature beats 2.5 (0 64) 0.001 86.5 (3286) 0.002 10.5 (0 34) 0.76
(beats/24 h)
Ventricular premature 0.0 (0 9) 0.009 8.0 (0 67) 0.003 0.0 (0 9) 0.96
beats (beats/24 h)
Results are expressed as median (range). P 0.05 was considered significant.
a
Controls vs. SCH patients before treatment by the Mann-Whitney U test.
b
SCH patients before vs. after treatment by Wilcoxon signed-rank test.
c
SCH patients after treatment vs. controls by the Mann-Whitney U test.
d
Six months after reaching the euthyroidism.

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Sgarbi et al. Subclinical Hyperthyroidism and Cardiac Effects J Clin Endocrinol Metab, April 2003, 88(4):16721677 1675

TABLE 4. Echocardiographic data in controls and in patients with subclinical hyperthyroidism (SCH) before and 6 months after
achieving stabilized euthyroidism by antithyroid treatment

SCH patients before SCH patients after

Parameters Controls (n 10) Pa Pb Pc
therapy (n 10) therapyd (n 10)
LV internal dimension at diastole (cm/m2) 2.5 (2.4 3.1) 0.56 2.65 (2.23.1) 0.69 2.7 (2.23.2) 0.44
LV internal dimension at systole (cm/m2) 1.53 (1.131.9) 0.97 1.54 (1.251.8) 0.92 1.6 (0.921.98) 0.85
IV septum thickness at diastole (cm) 0.70 (0.6 1.0) 0.02 0.90 (0.71.0) 0.008 0.75 (0.6 0.9) 0.73
LV posterior wall thickness at diastole (cm) 0.80 (0.6 1.0) 0.05 0.90 (0.8 1.0) 0.004 0.70 (0.6 1.0) 0.54
LV mass index (g/m2) 79.1 (50.6 92.3) 0.02 89.7 (65.8 105.6) 0.009 71.4 (58.390.8) 0.8
Peak E (cm/sec) 78 (67100) 0.9 83 (44 137) 0.99 75 (59 116) 0.85
Peak A (cm/sec) 79 (47 89) 0.64 78 (6396) 0.32 75 (34 110) 0.67
E/A ratio 0.97 (0.51.6) 0.67 0.94 (0.571.6) 0.23 1.05 (0.6 3.3) 0.42
Deceleration time (msec) 195.0 (80 260) 0.05 142.5 (90 205) 0.84 144 (100 220) 0.07
Acceleration time of early filling (msec) 75.0 (40 90) 0.15 57.0 (40 76) 0.46 67.0 (40 90) NS
Peak E deceleration rate (cm/sec2) 422.5 (166 517) 0.02 529.0 (184 891) 0.6 409.5 (290 909) 0.6
Isovolumetric relaxation time (msec) 85.0 (70 100) 0.08 93.5 (70 160) 0.2 81.5 (70 130) 0.54
Shortening fraction (%) 0.4 (0.32 0.54) 0.54 0.42 (0.33 0.47) 0.62 0.45 (0.33 0.61) 0.42
Ejection fraction (%) 0.71 (0.6 0.85) 0.5 0.74 (0.6 0.8) 0.6 0.76 (0.6 0.9) 0.44
VCF (circumferences/sec) 1.2 (0.9 1.7) 0.07 1.44 (1.11.7) 0.13 1.35 (0.9 1.7) 0.1
Cardiac index (liter/min/m2) 2.2 (1.6 3.7) 0.38 2.60 (1.4 4.8) 0.76 2.8 (1.73.6) 0.3
End-systolic wall stress (g/cm2) 53 (26 71) 0.76 50 (39 94) 0.62 50 (2790) 0.87
Results are expressed as median (range). LV, Left ventricular; IV, interventricular; VCF, velocity of circumferential fiber shortening; NS,
not significant. P 0.05 was considered significant.
a
Controls vs. SCH patients before treatment by the Mann-Whitney U test.
b
SCH patients before vs. after treatment by Wilcoxon signed-rank test.
c
SCH patients after treatment vs. controls by the Mann-Whitney U test.
d
Six months after reaching the euthyroidism.

2729), decreased quality of life (17), and mortality (30). fibrillation (36, 37). Furthermore, a single measurement of
However, despite the claims of several experts and editorials low serum TSH in individuals aged 60 yr or older was re-
(8 12, 16, 17, 3132), few prospective trials of early treatment cently associated with increased mortality, in particular due
for endogenous subclinical hyperthyroidism have been re- to circulatory and cardiovascular diseases (30).
ported (19 21). In the present study, our patients presented a significant
In the present study, our patients presented clinical man- increase in the mean heart rate, total number of beats during
ifestations similar to those observed in overt hyperthyroid- 24 h, and atrial and ventricular premature beats. Further-
ism. The high Wayne clinical index obtained in the patients more, TSH and FT4 correlated significantly with atrial and
was in a range in which the clinical diagnosis could be con- ventricular premature beats, indicating an influence of thy-
sidered doubtful. Nevertheless, the symptoms significantly roid function on cardiac-rhythm disturbances. Six months
improved or disappeared after reaching the euthyroid state, after reaching the euthyroidism, these heart rhythm abnor-
establishing an association among the symptoms and a mild malities significantly improved or disappeared, suggesting
thyrotoxic state. Similar findings were found in other studies, that an earlier antithyroid therapy might avoid the potential
but the patients were not submitted to a specific antithyroid progression to more complex arrhythmias. We did not ob-
treatment. Stott et al. (33) observed that elderly patients with serve atrial fibrillation in these patients because of their age
subclinical hyperthyroidism had mild symptoms on the (not so old) or the prevalence of supraventricular arrhyth-
Wayne clinical index that differed from those of euthyroid mia, reported to be higher in patients with exogenous sub-
controls. Furthermore, Biondi et al. (17) found a significant clinical hyperthyroidism than in patients with endogenous
prevalence of thyrotoxic symptoms in young and middle- subclinical hyperthyroidism (17). The mechanism by which
aged patients with endogenous subclinical hyperthyroidism. thyroid hormone induces rhythm disturbances is probably
Taken together with the results of the present study, these related in part to direct chronotropic effects and in part to
data demonstrate that subclinical hyperthyroidism is a indirect effects on the sympathoadrenergic system (5). These
symptomatic condition and can affect the quality of life. possibilities are supported by the present study using spe-
Subclinical hyperthyroidism has been associated with sev- cific antithyroid therapy and by others using -adrenergic
eral heart effects (13, 16, 34), but the main cardiovascular blockade (38).
morbidity is the atrial fibrillation (35). In the Framingham In this study, heart morphology was also compromised.
population, the relative risk of atrial fibrillation in elderly The patients with subclinical hyperthyroidism presented a
subjects with low serum TSH levels as compared with those mild increase in left ventricular mass index, reflected by
with normal TSH concentrations was 3.1 (14). These results increased interventricular septum thickness and left ventric-
indicate that subclinical hyperthyroidism is related to a ular posterior wall thickness at diastole, but it was not suf-
higher cardiovascular risk in older patients and raised the ficient to cause left ventricular hypertrophy. These results are
question of whether these patients should receive early treat- in accordance with Shapiro et al. (18). A significant reduction
ment to prevent atrial fibrillation. This dilemma is of great in the heart size was observed 6 months after stable normal-
clinical importance because the risk of arterial thromboem- ization of serum TSH concentration, indicating that this
bolism is increased in patients with thyrotoxicosis and atrial slight increase in the cardiac mass could probably progress

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1676 J Clin Endocrinol Metab, April 2003, 88(4):16721677 Sgarbi et al. Subclinical Hyperthyroidism and Cardiac Effects

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 nor-
mal range, suggesting that the clinical abnormalities might
be explained by thyroid hormone levels above the hypotha-
lamic-pituitary set point for the patient either by increased
thyroid hormone concentrations in organ tissues or by pos-
sible fluctuations in thyroid hormone secretion.
In patients with overt hyperthyroidism, there is an en-
hanced cardiac diastolic performance (41). Our data showed
that subclinical hyperthyroidism slightly affected diastolic
function, but no alteration was found after reaching euthy-
roidism. An impairment of diastolic function has been ob-
served (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, 2730), 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 pa-
tients and nonrandomized design, we believe that our find-
ings highlight that the euthyroid state was related to an
improvement of the clinical, laboratory, and cardiac distur-
bances. It suggests that early antithyroid therapy should be
FIG. 1. Effect of antithyroid treatment on echocardiographic findings considered in patients with endogenous subclinical hyper-
in endogenous subclinical hyperthyroid patients before (untreated thyroidism where it is needed to prevent potential progres-
patients) and six months after reaching the euthyroidism (euthyroid
patients) by methimazole treatment. Comparison with the control sion to a more advanced heart disease.
group. For each box plot, lines at the top, bottom and the middle of the
box correspond to 75th, 25th and 50th (median) percentile, respectively. Acknowledgments
The whiskers at the top and the bottom of the box extend from the 90th
and 10th percentile, respectively. LVMi, Left ventricular mass index. Received July 8, 2002. Accepted January 16, 2003.
LVPWT, Left ventricular posterior wall thickness. IVST, Interven- Address all correspondence and requests for reprints to: Prof. Joao
tricular septum thickness. g/m2, grams per square meter. cm, cen- Hamilton Romaldini, Avenida Indianopolis, 530. CEP 04062-000, Sao
timeters. The Mann-Whitney U test was performed to analyze the Paulo, Brazil. E-mail: jhroma@netpoint.com.br.
changes between patients and controls. The Wilcoxon signed-rank This work was presented in part at the 12th International Thyroid
test was performed to analyze the changes among patients with sub- Congress, Kyoto, Japan, 2000.
clinical hyperthyroidism before therapy and six months after reach-
ing the euthyroidism by methimazole therapy The P value less than
0.05 was considered significant. References
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to hypertrophy and that an early treatment might avoid the mental and clinical text, 7th ed. Philadelphia: Lippincott-Raven; 595707
2. Klein I 1990 Thyroid hormone and the cardiovascular system. Am J Med
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provoke left ventricular hypertrophy by combined direct 3. Woeber KA 1992 Thyrotoxicosis and the heart. N Engl J Med 327:94 98
4. Polikar R, Burger AG, Scherrer U, Nicod P 1993 The thyroid and the heart.
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