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Clinical Studies |
Divisions of Endocrinology, Diabetes and Metabolism, and Cardiology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York 10467
Address all correspondence and requests for reprints to: Martin I. Surks, M.D., Montefiore Medical Center, Division of Endocrinology, 111 E. 210th Street, Bronx, New York 10467. E-mail: surks{at}aecom.edu.yu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We were surprised by these findings because they did not seem compatible with our own experience when caring for thyroid cancer patients who were athyreotic and treated with TSH-suppressive doses of L-T4. Therefore, we studied 17 athyreotic patients treated with L-T4 at doses titrated to the point of TSH suppression. We determined the effect of L-T4 therapy on symptoms, mean heart rate, and occurrence of atrial and ventricular premature contractions as determined by Holter monitoring. In addition, patients underwent two-dimensional Doppler echocardiography to evaluate ventricular size and function during systole and diastole as well as the diastolic transmitral velocity filling profile. For each patient, a sex- and age-matched control without history of cardiac or thyroid disease was similarly studied.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The charts of patients of the Division of Endocrinology, Diabetes, and Metabolism at Montefiore Medical Center who had undergone thyroid ablative therapy for thyroid carcinoma were reviewed. Selection for study required documented thyroid ablation for thyroid cancer, L-T4 treatment at doses titrated to just suppress serum TSH for at least 1 yr, documented suppression of TSH to the limits of a third generation assay (used since 1988), no interruption of therapy over the previous 6 months, absence of hypertension, absence of heart disease, and absence of treatment with ß-adrenergic receptor blockers. Before 1988, the absence of a TSH response to injected TRH was the criterion used to establish TSH suppression (8). Patients who qualified were interviewed at random, and the first 17 patients to agree were entered into the study. As each patient was entered, an age-matched (±3 yr) and sex-matched control subject was recruited from professional and social acquaintances of the authors. The control subjects satisfied all inclusion criteria, except they had no history of thyroid disease. Patients and control subjects were studied in random chronological order after signing informed consent.
After a venous blood sample was obtained, they completed a questionnaire to assess symptoms of thyrotoxicosis. This questionnaire was based on a rating score devised by Klein et al. (9) in which scores of 0–4 were given to each of 10 categories of signs or symptoms of adrenergic tone. The rating score, identical to that used by Biondi et al. (5, 7) and Fazio et al. (6), has a maximal score of 40, and patients with thyrotoxicosis score between 19–28. To use this system as a subjective questionnaire, one category requiring objective assessment of the precordium was deleted. This resulted in a maximum score of 36. We do not believe that deletion of this category would affect our mean score, since it only applies when pulse rate is greater than 90 beats/min.
Subsequently, subjects underwent an echocardiogram and had a Holter monitor attached. The cardiology staff was blinded as to whether each subject was a patient or a control. The study protocol was approved by the Montefiore Medical Center’s institutional review board (protocol 1199504130).
Assays
Serum T4 was determined by a homogeneous enzyme immunoassay (EMIT-2000; Boehringer Mannheim Corp., Indianapolis, IN). Serum T3 was determined by a competitive immunoassay (Ciba-Corning Automated Chemiluminescence System, Ciba-Corning Diagnostics Corp., Medfield, MA). Free T4 estimate was measured by a one-site immunometric assay, and serum TSH was determined by a third generation assay using a chemiluminescence assay kit (both from Nichols Institute Diagnostics, San Juan Capistrano, CA). The intraassay coefficient of variation for each assay was less than 8%.
Holter analysis. Holter tapes were analyzed using a computer-based analyst-interactive system manufactured by Zymed C Corp. (Zymed model 1600). All tapes were overread by an electrophysiologist in a blinded fashion. Furthermore, all tapes were considered acceptable for analysis because they had at least 18 h of interpretable data.
Echocardiographic examination and data collection. M-Mode, two-dimensional images, and Doppler examination were obtained using a Hewlett-Packard Sonos 1500 (Hewlett-Packard, Andover, MA) connected to a 2.5-MHz transducer. All measurements were made with the patient in the left lateral decubitus position. Left ventricular (LV) dimensions were measured by M-mode at end systole and end diastole. The thicknesses of the septum and posterior basal free wall were measured at end diastole. All M-mode measurements were made according to the recommendation of the American Society of Echocardiography (10). LV mass was calculated using the following equation (11): LV mass = 1.04 [(LVIDd + PWTd)3 - LVIDd)3] - 13.6, where LVID is LV dimension, VST is ventricular septal thickness, PWT is posterior wall thickness, and d is diastole.
LV volumes and ejection fraction were calculated from two-dimensional echocardiographic apical view images at end systole and end diastole using the modified Simpson’s rule biplane method (12). LV volumes were indexed for body surface area derived from subjects’ height and weight. Mitral inflow velocities were recorded from the apical four-chamber view by positioning the pulsed wave Doppler sample volume at a level just proximal to the tips of mitral valve leaflets. Conventional and color flow Doppler were carried out to detect valvular regurgitation from standard echocardiographic views. Three indexes of LV filling were determined from the mitral inflow velocity profile: 1) maximal early diastolic flow velocity, 2) maximal late diastolic flow velocity, and 3) early to late filling velocities (E/A ratio). All measurements were made by two independent observers who were not aware of the subjects’ clinical data.
Statistics
Data are presented as the mean ± SD. Statistical analysis was carried out using Excel V 5.0, Microsoft (Redmond, WA). The significance of differences between means was determined by independent t test, and correlations between parameters was determined by Pearson correlation analysis.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. The patients ranged in age from 27–63 yr. The
duration of L-T4 therapy was 2.9–23 yr, with a
mean duration of 9.2 ± 5.4 yr. The mean
L-T4 dosage was 2.8 ± 0.9
µg/kg·day (0.192 ± 0.058 mg/day). The mean values for serum
thyroid hormone concentrations for patients and control subjects are
shown in Table 2. Mean serum T4
and free T4 estimates were increased in patients;
mean serum T3 levels were similar in the two groups. The
mean serum TSH concentration determined on the day of evaluation
confirmed the chart review that TSH was suppressed to near the limits
of assay detection (<0.01 µU/mL). All but one had serum TSH levels
from less than 0.01 to 0.06 µU/mL. One patient had a serum TSH level
of 0.18 µU/mL.
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Patients had minimal symptoms, but a significantly greater symptom
score than controls (4 ± 3 vs. 2 ± 1;
P < 0.05; Table 3). The range of
symptom scores for patients was 1–13, and that for controls was 0–4.
The maximum score possible on the symptom questionnaire is 36.
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The analysis of Holter monitoring is shown in Table 3
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with the minimal symptomatology in patients and controls, the mean
heart rate was similar in both groups. Similarly, there was no
influence of L-T4 treatment on the
incidence of atrial or ventricular premature contractions. The majority
of patients (70%) and controls (76%) had neither type of premature
contractions.
Doppler echocardiographic studies
The results of analysis of echocardiograms are shown in Table 4. There were no significant differences in measurements
of interventricular septum thickness or posterior wall thickness. The
mean ejection fraction measured by the modified Simpson rule was
identical in patients and controls. However, the mean left ventricular
mass index was significantly (P < 0.05) greater in
patients receiving L-T4. Analysis of
mean flow velocity rates of ventricular filling during diastole
revealed no significant difference between rates in early (E) or late
(A) diastole or in the E/A velocity ratio in patients compared to that
in control subjects.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In contrast to previously reported data, Holter monitor recording in our patients revealed no differences between patients and control subjects. Whereas previously studied patients had significant increases in mean heart rate (5, 6, 7), our patients did not. We characterized atrial and ventricular extrasystoles in the same manner as did Biondi et al. (5), but in contrast to their results, we did not find an increase in atrial premature contractions in our patients.
We carried out Doppler echocardiographic studies, which are routinely performed in our Medical Center, to assess ventricular function. We repeated some, but not all, of the measurements employed by previous studies. Thus, some measurements (isovolumic contraction and relaxation times, radiocircumferential fiber shortening) previously studied might reveal T4-induced abnormalities of a more subtle nature than we looked for.
Our patient population demonstrated a mitral inflow pattern indistinguishable from that of the age- and sex-matched control group. The Doppler mitral inflow pattern is a gradient-driven phenomenon; therefore, it is affected by changes in loading conditions as well as by physiological and technical factors, such as heart rate, sampling site, and associated valvular disease (12, 13, 14, 15). We did not confirm the finding that L-T4 treatment caused significant alteration of early or late ventricular filling. The widely used E/A ratio index is the result of a complex interplay of loading conditions, active and passive properties of cardiac chambers, pericardial properties, and right and left heart interaction. A change or abnormality in any of these factors could alter the LV diastolic filling profile without necessarily indicating or being associated with a specific disease process. Heart rate is an established factor that may affect the E/A ratio (16). In the paper by Biondi et al. (5), heart rate was significantly higher in the patient group than in controls. In addition, in their studies, LV systolic function was measured at the base of the LV chamber; more distal wall motion abnormalities may not be reflected by measurements taken at the base.
Indexes of LV systolic function were also similar in our patients and their controls. The mean ejection fraction was identical in both groups.
We confirmed previous reports of significantly increased LVMi in L-T4-treated patients. However, the mean LVMi of patients in our study was still within the normal limits defined by Devereaux et al. (17). Previous reports have shown reversal of LVMi in symptomatic patients treated with ß-adrenergic blockade (6). Because in our patients, this finding correlated with normal Holter monitoring and other echocardiographic evaluations, we do not consider it clinically significant to the individual patient. First, it will probably require serial studies, before and after L-T4 treatment, to understand whether this statistical finding has significance for individual patients. Secondly, in the absence of other indications for use of ß-adrenergic blockade, treatment of this finding alone would not seem justified. Thus, we do not recommend screening for this finding in the absence of symptoms of thyrotoxicosis or heart disease.
Although our mainly negative results of cardiac evaluation would seem to contradict the results of previous studies, it is not clear that we studied equivalent populations. Previous reports emphasize the coexistence of symptoms and cardiac abnormalities in a subset of L-T4-treated patients. Our patients were uniformly asymptomatic by clinical impression and only minimally different from controls by quantitative symptom questionnaire. Fazio et al. (6) reported that patients had an increased symptom score of 12.2 ± 3.9 compared to 4.2 ± 2.3 in control subjects (P < 0.001). They described this difference to be due to the "marked presence of palpitations, nervousness, tremor, heat intolerance and sweating" in the patient group. In contrast, although statistically increased above that in our control group (P < 0.02), our patients had a much lower mean symptom score (4 ± 2) than did patients reported by Fazio et al. (6).
Fazio et al. (6) reported that there was a significant relationship between the severity of symptoms and cardiac abnormalities in L-T4-treated patients. They reported that 40% (10 of 25) of their patients had symptom scores greater than 2 SD above the mean of the control group. They found that these patients with the highest symptoms scores had significantly increased ventricular size and late diastolic flow velocity compared to the rest of the patients. Moreover, Fazio et al. (7) recently reported that symptomatic patients had impaired cardiac reserve and exercise capacity. When we similarly classified our patients, only 24% (4 of 17 patients) had symptom scores greater than 2 SD above the mean of the control group, and the mean score of the control group (2 ± 1) was half that in previously reported patients. In contrast to the results of Fazio et al. (6), this subset of patients in our study had cardiac parameters statistically identical to those in the remaining patients (data not shown). It is likely that the level of symptomatology was too low in our patients for this analysis to correlate symptoms with cardiac abnormalities. In addition, our sample size is probably too small to show the absence of a small effect.
Thus, it appears that a subset of previously reported patients was more affected by TSH-suppressive therapy than other patients or the out-patients in this study. These patients stand out because they have symptoms of thyrotoxicosis. We recommend careful reevaluation of the L-T4 dose required for TSH suppression in symptomatic patients. If TSH suppression is not possible without coexisting symptoms of thyrotoxicosis, previous studies suggest a role for cardiac evaluation and treatment with ß-adrenergic blockade. However, as a result of our studies, we believe that careful clinical evaluation, short of cardiac laboratory studies, is sufficient to manage athyreotic patients with chronic TSH-suppressive therapy.
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Footnotes |
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Received January 30, 1997.
Revised April 23, 1997.
Accepted May 6, 1997.
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References |
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