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Original Studies |
Departments of Endocrinology (B.B., G.L.) and Internal Medicine (E.A.P., S.F., L.S.), University of Naples "Federico II" Medical School, 80131 Naples, Italy; and Department of Clinical and Experimental Medicine (C.C., M.N., S.F., F.P.), University of Catanzaro "Magna Grecia" Medical School, 88100 Catanzaro, Italy
Address correspondence and requests for reprints to: Dott.ssa Bernadette Biondi, Università degli Studi "Federico II" di Napoli, Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, via S. Pansini, 5, 80131 Napoli, Italy. E-mail: bebiondi{at}libero.it * Presented in part at the 72nd Annual
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Abstract |
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These data indicate that endogenous subclinical hyperthyroidism has a relevant clinical impact and that it affects cardiac morphology and function. Moreover, they suggest that treatment of persistent endogenous subclinical hyperthyroidism should be considered also in young and middle-aged patients to attenuate specific symptoms and signs of thyroid hormone excess, ameliorate the quality of life, and avoid the consequences to the heart of long exposure to a mild excess of thyroid hormone.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Subclinical hyperthyroidism is often present in patients treated with TSH-suppressive doses of Levo-thyroxine (L-thyroxine) for thyroid nodular disease or as postoperative treatment for differentiated thyroid carcinoma to prevent local and/or metastatic progression (exogenous subclinical hyperthyroidism). However, it is also seen in patients with autonomously functioning thyroid nodule or multinodular goiter (endogenous subclinical hyperthyroidism). Its prevalence, in several large community and clinical surveys, has been reported to range from 2–16% (2). The difference in reported rates of subclinical hyperthyroidism may be explained by the difference in sensitivity of TSH assays and by the different iodine intakes in the populations studied. In particular, endogenous subclinical hyperthyroidism represents a common disease in areas of iodine insufficiency (7).
The natural history of untreated multinodular goiter is characterized by progressive growth of one or more autonomous nodules and by a prolonged period of subclinical hyperthyroidism before development of overt thyrotoxicosis (7, 8, 9, 10, 11). The appearance of thyrotoxicosis may be precipitated by an increase in iodine intake from iodine-containing drugs or radiographic contrast agents. Iodine-induced thyrotoxicosis has been reported after the introduction of iodine prophylaxis in populations with endemic goiter (12, 13). Bourdoux et al. (14) have reported that after 2 yr of prophylaxis with iodine salt in Zaire, Africa, TSH was undetectable in the serum of 14% of 190 patients.
It has been demonstrated that overt hyperthyroidism affects cardiac performance and morphology (15, 16). In addition, the minimal but significant and persistent increase of thyroid hormone observed in patients with exogenous subclinical hyperthyroidism may affect the heart (17, 18, 19, 20, 21, 22, 23, 24, 25). However, it is not known whether there is the same effect in subjects with endogenous subclinical hyperthyroidism.
Therefore, in the present cross-sectional study, we have investigated whether, in young and middle-aged patients, endogenous subclinical hyperthyroidism: 1) induces specific symptoms and signs of thyroid hormone excess; 2) affects quality of life; and 3) produces cardiovascular abnormalities. This information is also important to establish whether this condition needs clinical surveillance or treatment.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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).
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). All had a sedentary lifestyle. The study was
approved by the Ethics Committee of the University of Naples
"Federico II." Assessment of thyroid status. The evaluation of thyroid morphology and function was performed by clinical examination, assessment of serum free thyroid hormone and TSH levels, 131I scintiscan, and ultrasound examination of the thyroid. Antithyroglobulin antibodies (normal range, <100 U/mL) were assayed with an immunoradiometric technique (Ares Serono kit set; Ares Serono, Milan, Italy), and antiperoxidase antibodies (normal range, <10 U/mL) were measured with a RIA kit (kit set; DiaSorin, Inc., Saluggia, Italy). Serum TSH levels were assessed by the sensitive TSH-immunoradiometric assay method (Delfia, Wallac, Inc. Finland), which has a detection limit of 0.03 mU/L (normal range, 0.3–3.8 mU/L; intraassay coefficient of variation, 3.7–5.4%). Serum free T4 and free T3 levels were assessed with the Lisophase kit (Technogenetics, Milan, Italy). The intra- and interassay variation and sensitivity was 2.9%, 4.7%, and 0.8 pmol/L for free T3 and 5.0%, 9.0%, and 1.0 pmol/L for free T4. Reference ranges in our laboratory are: free T3, 4.0–9.2 pmol/L; free T4, 7.7–20.6 pmol/L.
Assessment of symptoms and signs of thyroid hormone excess and quality of life. To evaluate the occurrence of specific symptoms and signs of thyroid hormone excess and to investigate general health, patients and control subjects were assessed by using the Symptom Rating Scale (SRS) (26) and were asked to complete (unaided) the Short Form 36 Health Survey (SF 36) (27). The SRS questionnaire was applied by two physicians, unaware of the study protocol (interphysician agreement: 92 ± 4%), higher scores indicating higher occurrence of specific symptoms and signs of thyroid hormone excess. The SF 36 was chosen on the basis of previous studies that showed its reliability, validity, and internal consistency in estimating quality of life (28). It analyzes both the mental [mental health, role-emotional, social-functioning scales (MCS)] and physical [physical functioning, role-physical, bodily pain scales (PCS)] components of well being, with higher scores indicating better health status.
Assessment of cardiac morphology and function
Electrocardiography. Standard 12-lead electrocardiograms (ECG) were recorded in all subjects. Evidence of left ventricular (LV) hypertrophy and conduction and repolarization abnormalities was assessed. Eighteen of the 23 endogenous subclinical hyperthyroid patients underwent 24-h ECG monitoring to detect rhythm disturbances; the tapes were printed with a full disclosed unit. After coding, the printouts were analyzed blindly by two observers (E.A.P. and C.C.). The subjects were then categorized according to the number and complexity of atrial premature beats as previously reported (18).
Doppler echocardiography. Complete M-mode and two-dimensional Doppler echocardiographic analysis was performed with an ultrasound mechanical system equipped with a 3.5-MHz transducer (Apogee CX, Interspec, Inc., Ambler, PA). M-mode and two-dimensional recordings were acquired with the patients in the lateral recumbent position, according to previously described methods (29). The investigator reading the echoes was blinded as to whether the recordings were of subclinical hyperthyroid or normal subjects. The following parameters were assessed on the M-mode recordings: LV end-diastolic and end-systolic diameters (LVEDD and LVESD, respectively), and LV posterior wall and interventricular septum thickness (PWT and IVST, respectively). LV mass was calculated by using the Penn convention, with the following regression-corrected cube formula (30): LVM = 1.04[(IVST + LVEDD + PWT)3 - (LVEDD)3]-14 g. LV fractional shortening (FS) was obtained by the following formula: FS = (LVEDD - LVESD)/LVEDD. Heart rate-adjusted mean velocity of circumferential fiber shortening was calculated by dividing the fractional shortening by the ejection time.
Doppler tracings were acquired during quiet respiration with the transducer positioned at, or slightly to the left of the cardiac apical impulse, according to a previously reported method (23). The following parameters were measured and calculated on mitral flow velocimetry: maximal early diastolic flow velocity (E), maximal late diastolic flow velocity (A), and the E/A ratio. Isovolumic relaxation time (i.e. the time interval from aortic valve closure to the onset of early diastolic flow) was obtained by simultaneous recording of aortic and mitral flow by continuous-wave Doppler at 100 mm/sec speed. Aortic peak flow velocity and mean aortic acceleration were obtained by aortic flow velocimetry. In particular, mean aortic acceleration was obtained by dividing the peak flow velocity by the acceleration time.
Statistical analysis. Data are reported as the mean ± SD. The two-tailed unpaired Student’s t test and linear regression were used for statistical analysis. The Fisher’s exact test was used to compare the prevalence of arrhythmias between groups. P less than 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. The
patients and the control subjects were well matched for body surface
area and systolic and diastolic blood pressure. Although in the normal
reference ranges mean serum free T3 and free
T4 estimates were significantly increased in the
patients as compared with the control subjects, whereas basal mean
serum TSH concentration was significantly lower. Assessment of symptoms and signs of thyroid hormone excess and quality of life
The mean SRS score, which evaluates specific symptoms and signs of
hyperthyroidism, was significantly higher in the group of patients than
in the control group (P < 0.001; Table 1). This was
principally accounted for by the higher prevalence of palpitations,
nervousness, tremor, heat intolerance, and sweating. The SF 36 scores
for both mental (MCS) and physical (PCS) components were also
significantly lower (both P < 0.001; Table 1) in the
patients than in the control subjects. A significant inverse
correlation was found between the SRS scores and the sums of the MCS
and PCS scores (r = -0.84, P = 0.008). No
correlation was found between thyroid function and the sums of the MCS
and PCS scores (data not shown).
Assessment of cardiac morphology and function
Electrocardiography. No ECG abnormality was detected in either
the controls or patients. All subjects were in sinus rhythm, and none
fulfilled the ECG criteria of LV hypertrophy. Holter analysis (Table 2) showed a significant increase in the
average heart rate in the patients as compared with that of the normal
subjects (82 ± 6 vs. 70 ± 6 bts;
P < 0.001). The prevalence of atrial premature beats
was higher in patients than in controls, but the difference was not
significant (78% vs. 67%; P = 0.852). No
difference was observed in the prevalence of ventricular
arrhythmias.
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, the mean interventricular septal
thickness and, to a greater extent, the mean LV posterior wall
thickness were significantly higher in the patients than in the
controls (P = 0.025 and P = 0.004,
respectively). As expected, the mean LV mass was significantly
increased in the patient group (162 ± 24 vs. 132
± 22 g; P < 0.001). The mean value of
end-diastolic diameter did not differ between the two groups
(P = 0.401), whereas the mean value of end-systolic
diameter was significantly decreased in hyperthyroid patients (29
± 3 vs. 31 ± 3 m;, P =
0.029).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The patients with endogenous subclinical hyperthyroidism evaluated in this study, as well as the patients with exogenous subclinical hyperthyroidism, had symptoms and signs of hyperthyroidism evaluated by the SRS score (18, 22, 25, 31). Similarly, a group of elderly patients with TSH levels less than 0.1 mU/L had a higher Wayne score (a clinical index of hyperthyroidism) compared with a group 10 euthyroid subjects (32). Our patients with endogenous subclinical hyperthyroidism also had lower mental and physical scores as assessed by the SF 36, indicating that their quality of life was impaired compared with control subjects. Interestingly, SRS and SF 36 scores were significantly and inversely correlated (r = -0.84; P < 0.01), thus suggesting that the impairment of quality of life observed in these patients was principally due to the higher prevalence of thyroid hormone excess-related symptoms and signs. Conversely, there was no significant correlation between thyroid function and the sums of the mental and the physical component scores of the SF 36. However, this result is not surprising because each patient probably had a different sensitivity to the mild excess of thyroid hormone.
The cardiac effects of exogenous subclinical hyperthyroidism induced by long-term L-thyroxine suppressive TSH therapy (17, 18, 19, 20, 21, 22, 23, 24, 25) have been widely studied. In these patients it has been demonstrated that chronic exposure to a mild excess of thyroid hormones was responsible for an increase in LV mass (18, 21, 22, 25). We previously showed that the increase in LV mass was principally the consequence of the chronic increase in cardiac workload, and was responsible for the attendant diastolic dysfunction and impaired systolic function during exercise (23, 24). These abnormalities were significantly reverted by ß-blocking drugs (31). The prognostic significance of the demonstrated increase in LV mass in patients with exogenous and endogenous subclinical hyperthyroidism remains unknown because of the lack of epidemiological studies of the cardiovascular risk in these patients. However, it is well known that LV hypertrophy is an independent risk factor for cardiovascular morbidity and mortality (33). In addition, increased LV mass, not necessarily above the hypertrophic threshold, has been found to be associated with increased risk of sudden death in subjects 45 yr of age or older(34).
Results concerning the increase of heart rate and the incidence of supraventricular arrhythmias in patients with exogenous subclinical hyperthyroidism are not consistent (1, 18, 19, 20, 21, 22, 25, 31, 35). Our previous data obtained with Holter ECG in patients affected by exogenous subclinical hyperthyroidism revealed higher 24-h mean heart rates, increased prevalence of premature atrial contractions, and, in predisposed subjects, episodes of reentrant atrioventricular nodal tachycardia (18, 19, 20). In endogenous subclinical hyperthyroidism, despite a significant increase in heart rate, we did not find a significant prevalence of atrial premature contractions. In this regard, it must be emphasized that endogenous subclinical hyperthyroidism may be significantly different from exogenous subclinical hyperthyroidism in terms of both rate and duration of rise in thyroid hormones. This might explain why the incidence of supraventricular arrhythmias was higher in patients with exogenous subclinical hyperthyroidism than in those with endogenous hyperthyroidism. However, also in these patients, the mild excess of thyroid hormone was, in all likelihood, sufficient to directly stimulate sino-atrial node function and to account for the increase in heart rate reported in the present study and in the pioneering study of Boutin et al. (35).
The regulation of heart rate by thyroid hormone is complex. The effects of an excess of thyroid hormone are related, in part, to an indirect adrenergic effect and, in part, to a direct intrinsic positive chronotropic effect (36, 37). In fact, in rat myocardium, thyroid hormone regulates the shaker-related potassium channel mRNA levels, and recently it has been reported that myocardial hyperpolarization-activated cyclic nucleotide-gated channel (HCN2) mRNA is thyroid hormone dependent (38).
The significant increase in heart rate has implications in young and middle-aged patients affected by subclinical hyperthyroidism. Indeed, enhanced heart rate has been shown to be associated with increased risk of cardiovascular and noncardiovascular mortality also in middle-aged subjects (39, 40).
Taken together, the results of the present study, coupled with those previously reported, suggest that many patients with subclinical hyperthyroidism, be it exogenous or endogenous, are symptomatic and support the claim that the term "subclinical" hyperthyroidism is a misnomer (11, 41). Moreover, the occurrence of cardiovascular abnormalities in subclinical hyperthyroid patients emphasizes that subclinical hyperthyroidism should be considered de facto a mild form of tissue thyrotoxicosis.
Treatment of subclinical hyperthyroidism is still controversial, particularly as regards young and middle-aged people (2, 3, 4, 5, 6). Treatment is recommended in older patients with even mild symptoms of thyrotoxicosis, and risk factors for cardiovascular or skeletal diseases, or a large goiter. Exogenous or endogenous subclinical hyperthyroidism in older patients represents an important risk factor for atrial fibrillation (1). Because increased morbidity and mortality from thromboembolic events is associated with atrial fibrillation, subclinical hyperthyroidism in older patients may be considered a risk factor for thromboembolism. However, also young and middle-aged patients with untreated endogenous subclinical hyperthyroidism are at risk of untoward events: 1) impairment of quality of life, related to the persistence of symptoms and signs of hyperthyroidism; 2) adverse cardiac effects, related to both the increased LV mass and increased heart rate; 3) cardiovascular risks, related to the onset of overt thyrotoxicosis in hearts previously exposed to prolonged periods of subclinical hyperthyroidism.
In conclusion, these data suggest that early treatment of persistent endogenous subclinical hyperthyroidism should be considered not only in older but also in young and middle-aged patients to improve their quality of life and avoid the consequences of long-term exposure of the cardiovascular system to small increases in thyroid hormone.
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Acknowledgments |
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Received April 27, 2000.
Revised August 10, 2000.
Accepted August 30, 2000.
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