Minimal Cardiac Effects in Asymptomatic Athyreotic Patients Chronically Treated with Thyrotropin-Suppressive Doses of L-Thyroxine1
L. E. Shapiro,
R. Sievert,
L. Ong,
E. L. Ocampo,
R. A. Chance,
M. Lee,
M. Nanna,
K. Ferrick and
M. I. Surks
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
Biondi, Fazio, and colleagues recently reported that long term
T4treatment to suppress serum TSH markedly
affects cardiac function.T4-treated patients had
more symptoms [12.2 ± 3.9 (±SD)vs.
4.2 ± 2.3 by quantitative questionnaire], highermean heart
rate, increased incidence of atrial extrasystoles,increased
interventricular septal thickness and left ventricularmass index
(LVMi), and significant diastolic dysfunction. Theseverity of cardiac
abnormalities was highly correlated withscores of a rating scale used
for assessing symptoms of thyrotoxicosis.We have duplicated their
studies in 17 athyreotic patients (meanage, 45 ± 10 yr; range,
27–63 yr) without heartdisease or hypertension whose dose of
T4 was titrated to suppressserum TSH to less
than 0.01 µU/mL. The mean duration ofT4
treatment was 9.2 ± 5.4 yr. Controls were healthyvolunteers
matched for sex and age (±3 yr). The meanT4
dose was 2.8 ± 0.9 µg/kg (0.192 ± 0.058mg/day). By
questionnaire, patients had minimal symptoms, althoughtheir symptom
score was significantly greater than the controlvalue (4 ± 3
vs. 2 ± 1; P < 0.05; maximum
score,36). No differences in mean heart rate or in atrial or
ventricularextrasystoles were noted. In patients, indexes of systolic
anddiastolic function and interventricular septal thickness were
similarto control values. The mean LVMi was normal in both groups.
However,the mean LVMi in patients (117 ± 35 g/m2)
was higherthan that in controls (92 ± 31; P
< 0.05). In conclusion,patients were minimally affected by
TSH-suppressive doses ofT4. They had few
symptoms and no increase in extrasystoles orbasal heart rate. Based on
current knowledge, the increase inLVMi observed in patients without
associated significant systolicor diastolic abnormalities does not
have clinical or prognosticimportance. Therefore, in the absence of
symptoms of thyrotoxicosis,patients treated with TSH-suppressive doses
of L-T4 may be followedclinically
without specific cardiac laboratory studies.
CARDIAC manifestations are prominent
features in the historyand physical examination of patients with
thyrotoxicosis. Thyrotoxicosiscan exacerbate the manifestations of
coexisting heart disease,and cardiac function may be abnormal in
thyrotoxic patientswithout coexisting heart disease (1, 2, 3, 4). However,
minimalelevations of thyroid hormones, like those in some
L-T4-treatedpatients, are usually
well tolerated and have uncertain cardiaceffects. Recent reports have
described the cardiac effects ofchronic
L-T4 therapy at doses that result in
minimal thyroidhormone excess, defined by suppression of TSH to the
limitsof current ultrasensitive assays (5, 6, 7). In these studies,the
goal of TSH suppression was to treat patients with eithernontoxic
goiters (the majority) or thyroid cancer after thyroidablation. The
researchers reported a remarkable incidence ofsymptoms, suggesting
adrenergic overactivity, and a significantincrease in mean basal heart
rate and atrial premature contractions.Furthermore, they reported
significant abnormalities in ventriculardiastolic relaxation and
exercise capacity. Finally, they demonstratedthe benefit of using
ß-adrenergic blockade in treatingsymptoms of thyrotoxicosis as well
as correcting cardiac abnormalitiesfound in symptomatic patients.
We were surprised by these findings because they did not seem
compatiblewith our own experience when caring for thyroid cancer
patientswho were athyreotic and treated with TSH-suppressive doses of
L-T4.Therefore, we studied 17
athyreotic patients treated with L-T4
atdoses titrated to the point of TSH suppression. We determinedthe
effect of L-T4 therapy on symptoms,
mean heart rate, andoccurrence of atrial and ventricular premature
contractionsas determined by Holter monitoring. In addition, patients
underwenttwo-dimensional Doppler echocardiography to evaluate
ventricularsize and function during systole and diastole as well as
thediastolic transmitral velocity filling profile. For each patient,a
sex- and age-matched control without history of cardiac orthyroid
disease was similarly studied.
The charts of patients of the Division of Endocrinology,
Diabetes,and Metabolism at Montefiore Medical Center who had undergone
thyroidablative therapy for thyroid carcinoma were reviewed. Selection
forstudy required documented thyroid ablation for thyroid cancer,
L-T4treatment at doses titrated to
just suppress serum TSH for atleast 1 yr, documented suppression of
TSH to the limits of athird generation assay (used since 1988), no
interruption oftherapy over the previous 6 months, absence of
hypertension,absence of heart disease, and absence of treatment with
ß-adrenergicreceptor blockers. Before 1988, the absence of a TSH
responseto injected TRH was the criterion used to establish TSH
suppression(8). Patients who qualified were interviewed at random, and
thefirst 17 patients to agree were entered into the study. As each
patientwas entered, an age-matched (±3 yr) and sex-matched control
subjectwas recruited from professional and social acquaintances ofthe
authors. The control subjects satisfied all inclusion criteria,except
they had no history of thyroid disease. Patients andcontrol subjects
were studied in random chronological orderafter signing informed
consent.
After a venous blood sample was obtained, they completed a
questionnaireto assess symptoms of thyrotoxicosis. This questionnaire
wasbased on a rating score devised by Klein et al. (9) in
whichscores of 0–4 were given to each of 10 categories of signsor
symptoms of adrenergic tone. The rating score, identicalto that used
by Biondi et al. (5, 7) and Fazio et al. (6), has
amaximal score of 40, and patients with thyrotoxicosis scorebetween
19–28. To use this system as a subjective questionnaire,one category
requiring objective assessment of the precordiumwas deleted. This
resulted in a maximum score of 36. We do notbelieve that deletion of
this category would affect our meanscore, since it only applies when
pulse rate is greater than90 beats/min.
Subsequently, subjects underwent an echocardiogram and had aHolter
monitor attached. The cardiology staff was blinded asto whether each
subject was a patient or a control. The studyprotocol was approved by
the Montefiore Medical Center’sinstitutional review board (protocol
1199504130).
Assays
Serum T4 was determined by a homogeneous
enzyme immunoassay(EMIT-2000; Boehringer Mannheim Corp., Indianapolis,
IN). SerumT3 was determined by a competitive immunoassay
(Ciba-CorningAutomated Chemiluminescence System, Ciba-Corning
DiagnosticsCorp., Medfield, MA). Free T4
estimate was measured by a one-siteimmunometric assay, and serum TSH
was determined by a thirdgeneration assay using a chemiluminescence
assay kit (both fromNichols Institute Diagnostics, San Juan
Capistrano, CA). Theintraassay coefficient of variation for each assay
was lessthan 8%.
Holter analysis.
Holter tapes were analyzed using a
computer-based analyst-interactivesystem manufactured by Zymed C Corp.
(Zymed model 1600). Alltapes were overread by an electrophysiologist
in a blinded fashion.Furthermore, all tapes were considered acceptable
for analysisbecause they had at least 18 h of interpretable
data.
Echocardiographic examination and data collection.
M-Mode,
two-dimensional images, and Doppler examination wereobtained using a
Hewlett-Packard Sonos 1500 (Hewlett-Packard,Andover, MA) connected to
a 2.5-MHz transducer. All measurementswere made with the patient in
the left lateral decubitus position.Left ventricular (LV) dimensions
were measured by M-mode atend systole and end diastole. The
thicknesses of the septumand posterior basal free wall were measured
at end diastole.All M-mode measurements were made according to the
recommendationof the American Society of Echocardiography (10). LV
mass wascalculated 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
echocardiographicapical view images at end systole and end diastole
using themodified Simpson’s rule biplane method (12). LV volumeswere
indexed for body surface area derived from subjects’height and
weight. Mitral inflow velocities were recorded fromthe apical
four-chamber view by positioning the pulsed waveDoppler sample volume
at a level just proximal to the tips ofmitral valve leaflets.
Conventional and color flow Doppler werecarried out to detect valvular
regurgitation from standard echocardiographicviews. Three indexes of
LV filling were determined from themitral inflow velocity profile: 1)
maximal early diastolic flowvelocity, 2) maximal late diastolic flow
velocity, and 3) earlyto late filling velocities (E/A ratio). All
measurements weremade by two independent observers who were not aware
of thesubjects’ clinical data.
Statistics
Data are presented as the mean ± SD.
Statistical analysiswas carried out using Excel V 5.0, Microsoft
(Redmond, WA).The significance of differences between means was
determinedby independent t test, and correlations between
parameters wasdetermined by Pearson correlation analysis.
The characteristics of the patients are shown in Table 1. Thepatients ranged in age from 27–63 yr. The
duration ofL-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
thyroidhormone concentrations for patients and control subjects are
shownin Table 2. Mean serum T4
and free T4 estimates were increasedin patients;
mean serum T3 levels were similar in the two groups.The
mean serum TSH concentration determined on the day of evaluation
confirmedthe chart review that TSH was suppressed to near the limits
ofassay detection (<0.01 µU/mL). All but one had serumTSH levels
from less than 0.01 to 0.06 µU/mL. One patienthad a serum TSH level
of 0.18 µU/mL.
Table 2. Hormonal pattern in patients during
L-T4 suppressive therapy and in the control
group
Symptom score questionnaire
Patients had minimal symptoms, but a significantly greater symptom
scorethan controls (4 ± 3 vs. 2 ± 1;
P < 0.05; Table3). The range of
symptom scores for patients was 1–13,and that for controls was 0–4.
The maximum score possibleon the symptom questionnaire is 36.
The analysis of Holter monitoring is shown in Table 3. Consistent
withthe minimal symptomatology in patients and controls, the mean
heartrate was similar in both groups. Similarly, there was no
influenceof L-T4 treatment on the
incidence of atrial or ventricularpremature 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 Table4. There were no significant differences in measurements
ofinterventricular septum thickness or posterior wall thickness.The
mean ejection fraction measured by the modified Simpsonrule was
identical in patients and controls. However, the meanleft ventricular
mass index was significantly (P < 0.05)greater in
patients receiving L-T4. Analysis of
mean flow velocityrates of ventricular filling during diastole
revealed no significantdifference between rates in early (E) or late
(A) diastole orin the E/A velocity ratio in patients compared to that
in controlsubjects.
Before this study, it was our impression that patients chronically
treatedwith TSH-suppressive doses of
L-T4 were usually free of symptoms
andsigns of thyrotoxicosis. Recent reports of cardiac abnormalitiesin
similarly treated patients provoked two questions. We wonderedwhy a
significant subset of reported patients had marked symptomsof
thyrotoxicosis (6, 7), whereas we considered our patientsto be
asymptomatic. This is a key difference between our patientsand those
previously studied. Cardiac abnormalities were concentratedin
symptomatic patients in published reports, and only in symptomatic
patientswas the beneficial effect of ß-adrenergic blockade
demonstrated(6). We also wondered if cardiac abnormalities were
presentin our clinically well patients treated with TSH-suppressive
dosesof L-T4. Although we could not
explain the significant incidenceof thyrotoxic symptoms in prior
studies, we found minimal cardiaceffects due to TSH-suppressive
therapy in our asymptomatic patients.
In contrast to previously reported data, Holter monitor recordingin
our patients revealed no differences between patients andcontrol
subjects. Whereas previously studied patients had significantincreases
in mean heart rate (5, 6, 7), our patients did not.We characterized
atrial and ventricular extrasystoles in thesame manner as did Biondi
et al. (5), but in contrast to theirresults, we did not
find an increase in atrial premature contractionsin our patients.
We carried out Doppler echocardiographic studies, which areroutinely
performed in our Medical Center, to assess ventricularfunction. We
repeated some, but not all, of the measurementsemployed by previous
studies. Thus, some measurements (isovolumiccontraction and relaxation
times, radiocircumferential fibershortening) previously studied might
reveal T4-induced abnormalitiesof a more subtle nature
than we looked for.
Our patient population demonstrated a mitral inflow pattern
indistinguishablefrom that of the age- and sex-matched control group.
The Dopplermitral inflow pattern is a gradient-driven phenomenon;
therefore,it is affected by changes in loading conditions as well as
byphysiological and technical factors, such as heart rate, sampling
site,and associated valvular disease (12, 13, 14, 15). We did notconfirm the
finding that L-T4 treatment caused
significant alterationof early or late ventricular filling. The widely
used E/A ratioindex is the result of a complex interplay of loading
conditions,active and passive properties of cardiac chambers,
pericardialproperties, and right and left heart interaction. A change
orabnormality in any of these factors could alter the LV diastolic
fillingprofile without necessarily indicating or being associated with
aspecific disease process. Heart rate is an established factorthat
may affect the E/A ratio (16). In the paper by Biondi etal.
(5), heart rate was significantly higher in the patientgroup than in
controls. In addition, in their studies, LV systolicfunction was
measured at the base of the LV chamber; more distalwall motion
abnormalities may not be reflected by measurementstaken at the
base.
Indexes of LV systolic function were also similar in our patientsand
their controls. The mean ejection fraction was identicalin both
groups.
We confirmed previous reports of significantly increased LVMiin
L-T4-treated patients. However, the
mean LVMi of patientsin our study was still within the normal limits
defined by Devereauxet al. (17). Previous reports have
shown reversal of LVMi insymptomatic patients treated with
ß-adrenergic blockade(6). Because in our patients, this finding
correlated with normalHolter monitoring and other echocardiographic
evaluations, wedo not consider it clinically significant to the
individualpatient. First, it will probably require serial studies,
beforeand after L-T4 treatment, to
understand whether this statisticalfinding has significance for
individual patients. Secondly,in the absence of other indications for
use of ß-adrenergicblockade, treatment of this finding alone would
not seem justified.Thus, we do not recommend screening for this
finding in theabsence of symptoms of thyrotoxicosis or heart
disease.
Although our mainly negative results of cardiac evaluation wouldseem
to contradict the results of previous studies, it is notclear that we
studied equivalent populations. Previous reportsemphasize the
coexistence of symptoms and cardiac abnormalitiesin a subset of
L-T4-treated patients. Our patients
were uniformlyasymptomatic by clinical impression and only minimally
differentfrom controls by quantitative symptom questionnaire. Fazio
etal. (6) reported that patients had an increased symptom
scoreof 12.2 ± 3.9 compared to 4.2 ± 2.3 in control
subjects(P < 0.001). They described this difference
to be due tothe "marked presence of palpitations, nervousness,
tremor, heatintolerance 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
relationshipbetween the severity of symptoms and cardiac abnormalities
inL-T4-treated patients. They
reported that 40% (10 of 25) oftheir patients had symptom scores
greater than 2 SD above themean of the control group. They
found that these patients withthe highest symptoms scores had
significantly increased ventricularsize and late diastolic flow
velocity compared to the rest ofthe patients. Moreover, Fazio et
al. (7) recently reported thatsymptomatic patients had impaired
cardiac reserve and exercisecapacity. When we similarly classified our
patients, only 24%(4 of 17 patients) had symptom scores greater than
2 SD abovethe mean of the control group, and the mean
score of the controlgroup (2 ± 1) was half that in previously
reported patients.In contrast to the results of Fazio et
al. (6), this subsetof patients in our study had cardiac
parameters statisticallyidentical to those in the remaining patients
(data not shown).It is likely that the level of symptomatology was too
low inour patients for this analysis to correlate symptoms with
cardiacabnormalities. In addition, our sample size is probably too
smallto show the absence of a small effect.
Thus, it appears that a subset of previously reported patientswas more
affected by TSH-suppressive therapy than other patientsor the
out-patients in this study. These patients stand outbecause they have
symptoms of thyrotoxicosis. We recommend carefulreevaluation of the
L-T4 dose required for TSH
suppression insymptomatic patients. If TSH suppression is not possible
withoutcoexisting symptoms of thyrotoxicosis, previous studies suggest
arole for cardiac evaluation and treatment with ß-adrenergic
blockade.However, as a result of our studies, we believe that careful
clinicalevaluation, short of cardiac laboratory studies, is sufficient
tomanage athyreotic patients with chronic TSH-suppressive therapy.
Footnotes
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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
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Abstract
Introduction
