The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 8 2410-2413
Copyright © 1997 by The Endocrine Society
Medical Therapy of Graves’ Disease: Does Thyroxine Prevent Recurrence of Hyperthyroidism?
A. Lucas,
I. Salinas,
F. Rius,
E. Pizarro,
M.L. Granada,
M. Foz and
A. SanmartÍ
Endocrinology Service (A.L., I.S., F.R., E.P., M.F., A.S.) and
Biochemistry Laboratory (M.L.G.), Hospital Universitari "Germans
Trias i Pujol," Badalona, Barcelona, Catalonia, Spain
Address correspondence and requests for reprints to: Dr. A. Lucas, Endocrinology Service, Hospital Universitari "Germans Trias i Pujol," Crta. Canyet s/n, 08916 Badalona, Barcelona, Catalonia, Spain.
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Abstract
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Sixty patients with Graves’ disease (GD) hyperthyroidism were
distributed in two randomized groups. Patients in group A (n = 30)
received carbimazole by a titration regimen, and patients in group B
(n = 30) were treated with higher doses of carbimazole plus
T4. Clinical and analytical evaluations were done at
baseline, during treatment (18.4 ± 2.6 months), and after, until
the relapse of hyperthyroidism, or for 4.98 ± 1.6 yr in patients
who did not relapse.
There were no differences in clinical parameters, thyroid hormones, or
TSH binding inhibitory immunoglobulins (TBII) levels between the two
groups, either at baseline or at the end of treatment. Serum TSH
persisted undetectable in 16 out of 60 patients (group A: 9; group B:
7), after treatment. Relapse occurred in 38 patients (63.3%), (group
A: 18 (60%) vs. group B: 20 (66.7%)). Patients who
relapsed had bigger goiters at baseline (P = 0.02) and at
the end of treatment (P = 0.03). Eighty-seven percent
(14/16) of patients with undetectable TSH after therapy relapsed,
vs. 54.5% (24/44) of those with normal TSH (P =
0.01). Undetectable TSH at the end of treatment was the only
independent variable in the logistic analysis to predict relapse.
Treatment modality did not influence the relapse rate.
This study has found that, in Spanish patients, the use of high doses
of carbimazole with T4 offers no advantages in the
treatment of GD hyperthyroidism.
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Introduction
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THE MOST frequent therapeutic policy in
Europe to achieve euthyroidism in Graves’ disease (GD) hyperthyroidism
is to use antithyroid drugs (ATD) over a period of several months.
Objectives of this treatment are to control hyperthyroidism and to
induce long-term remission in patients with a first episode of
hyperthyroidism (1). The most common method of treatment with ATD is
the so-called titration regimen. Regarding the likelihood of a
long-term remission after ATD therapy, results are conflicting with
reported rates ranging from 25–90% (2, 3, 4). Clinical findings weakly
associated with remission are small goiter size and a recent onset of
the hyperthyroidism symptoms when ATD therapy is initiated. However,
there are no reliable tests for predicting a lasting remission at the
time of diagnosis or after ATD treatment (3, 5). Factors that might
affect the frequency of GD remission are dosage and duration of ATD
therapy (6, 7, 8), so most clinicians recommend prolonged ATD treatment,
from 1 to 2 yr (2, 6, 9). Evidence that high doses of ATD have an
immunosuppressive effect (10, 11, 12, 13) has led some clinicians to use an
alternative regimen, maintaining high doses of ATD throughout the
entire treatment period and adding thyroxine to prevent iatrogenic
hypothyroidism. This regimen might be advantageous in avoiding relapse
by increasing immunosuppression, or by a possible effect of thyroxine
itself (8), although recent studies have reported no difference in
relapse rates between patients treated only with methimazole or with
methimazole and thyroxine (4, 14, 15, 16).
The present study was undertaken to evaluate the effects on
recurrence rates during a long observation period of carbimazole plus
thyroxine in patients with GD hyperthyroidism.
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Subjects and Methods
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The study was conducted in 60 consecutive untreated patients (11
men and 49 women, ages 7–57 yr, mean 36.0 ± 11.5) with initial
episode of GD hyperthyroidism, recruited from our outpatient Endocrine
Clinic. All patients lived in an area of normal iodine intake (17).
Diagnosis of GD was based on measurements of serum total
T3, T4, free T4 and TSH, nodulation
absence by thyroid palpation, and demonstration of a diffuse increased
thyroid uptake of 99mTcO4 (pertechnetate).
Patients were randomized by using sequentially numbered, sealed
envelopes containing cards indicating the treatment to be used, and
they were divided into 2 groups: A (n = 30) and B (n = 30).
All patients received carbimazole at an initial dose of 45–60 mg/day
(42.8 ± 8.4). When analytical euthyroidism was achieved in group
A, carbimazole was adjusted to maintenance doses, determined by
clinical evaluation and restoration of normal circulating free
T4 and total T3 concentrations. When patients
in group B became euthyroid, they received 30–45 mg/day carbimazole
plus 100 µg/day levothyroxine, adjusted after 1 month to doses
ranging from 75–150 µg/day (128.8 ± 27.2) to maintain normal
serum free T4 and total T3. Patients were
treated for a period of 12–24 months (18.4 ± 2.6). Clinical and
analytical evaluation was done before treatment, monthly during the
first 3 months, subsequently at 3-month intervals, and immediately
before treatment withdrawal. Post-treatment follow-up was done at a
3-month interval during the first 2 yr and annually thereafter or at
the moment of relapse of hyperthyroidism, if it occurred. Relapse after
carbimazole withdrawal was defined as recurrence or persistence of
abnormal thyroid hormones requiring further treatment. Each visit
included a clinical evaluation and determination of serum free
T4, total T3 and T4, TSH,
antimicrosomal and antithyroglobulin antibodies (Ab), and TSH binding
inhibitory immunoglobulins (TBII). The study was approved by the
Hospital Ethics Committee, and all patients signed an informed consent
for their inclusion.
Goiter size was estimated by palpation and classified into grades: G0,
impalpable or just palpable; G1, easily palpable; G2, visible on
inspection; and G3, visible at a distance. Ophthalmopathy was
classified using the "Classification of Eye Changes in Graves’
Disease of the American Thyroid Association" (18). Commercially
available kits were used to measure, radioimmunoassay, by RIA, serum
concentrations of free T4 (Behringwerke, Berlin, Germany),
total T3 and T4 (Diagnostic Products
Corporation, Los Angeles, CA), and TSH by immunoradiometric assay
(Behringwerke). Normal levels were, respectively: free T4
0.6–2 ng/dL; total T3 0.85–1.75 ng/mL; total
T4 4.5–12.5 µg/dL, and TSH 0.4–5 µU/mL. Serum
antimicrosomal and antithyroglobulin Ab were determined by Thymune
M-microsomal and T-Thyroglobulin Wellcome kits (Wellcome Diagnostics,
Bekenham, UK). Positive levels were, respectively: more than 1/100 and
more than 1/80. TBII levels were determined by a commercial kit
(TRAK-Assay; Brahms, Berlin, Germany; normal values <14 IU/L).
Data were analyzed using the two-tailed t-test or the
2 test as appropriate. Significance was defined as a
P < 0.05. Results are expressed as mean ±
SD. Logistic regression analysis was used for multivariate
analysis. Statistical analyses were performed with an SPSS packet.
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Results
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Characteristics of patients at baseline are shown in Table 1
. There were no differences in sex, age, goiter size,
ophthalmopathy, thyroid hormone, antithyroglobulin Ab, or TBII levels
between the 2 groups. Patients in group A showed a shorter evolution of
symptomatology (P = 0.04) and a lower frequency of
positive antimicrosomal Ab (P = 0.03). Fifteen patients
with positive TBII (10 in group A and 5 in group B) had free
T4 values higher than the patients with negative TBII
(6.62 ± 3.24 vs. 4.89 ± 2.38 ng/dL;
P = 0.036), although the T3 values were not
significantly different (4.32 ± 1.84 vs. 3.99 ±
1.53 ng/mL; P = 0.504). In any case, in spite of the
poor positivity of antibodies, and regarding free T4 and
T3 values at baseline (see Table 1), we can affirm that all
patients had severe GD hyperthyroidism.
Table 2 shows patients’ characteristics at withdrawal
of ATD therapy. No differences were observed in the parameters
evaluated. At the time of ATD withdrawal, serum TSH persisted
undetectable in 16 out of 60 patients (group A: 9; group B: 7).
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Table 2. Clinical and analytical data in Graves’ disease
hyperthyroid patients at the end of antithyroid drug therapy
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Relapse occurred 8.5 ± 9.7 months after withdrawal of ATD therapy
in 38 patients (63.3%), with no significant differences between groups
(group A: 18 (60%) vs. group B: 20 (66.7%) and with
similar clinical courses (data not shown). Most patients relapsed (15
in each group) during the first year posttreatment. As shown in Tables 3 and 4, patients who relapsed had bigger
goiters at baseline (P = 0.02) and at the end of
treatment (P = 0.03). Eighty-seven percent (14/16) of
patients with undetectable TSH after therapy relapsed, vs.
54.5% (24/44) of those with normal TSH (P = 0.01).
Patients with initially big goiters (G2–G3) persisted with
undetectable TSH at the end of ATD therapy in a larger number than
those without goiter (P = 0.002). Undetectable TSH at
the end of treatment was the only independent variable in the logistic
analysis to predict relapse. Treatment modality did not influence it.
Patients who did not relapse (n = 22) have been followed for
4.98 ± 1.6 yr (1.8–7).
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Table 3. Clinical and analytical data in Graves’ disease
hyperthyroid patients at baseline, comparing patients who relapsed with
those who did not, after 4.9 ± 1.6 yr of follow-up
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Table 4. Clinical and analytical data in Graves’ disease
hyperthyroid patients at the end of antithyroid drug therapy
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Discussion
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The main action of thionamides is to inhibit thyroid hormone
biosynthesis, but some studies have reported that these drugs at high
doses may affect the immunogenic response in GD and modify its natural
history, increasing its remission rate (7, 8, 11, 12, 13, 19). As has been
extensively reviewed (20), several studies support the possible
immunomodulatory effects of ATD (8, 10, 12, 16, 21, 22). Nonetheless,
some authors have failed to show the influence of ATD on
immunosuppressive mechanisms (23, 24), while others were unsuccessful
in relating higher methimazole oral doses to its intrathyroidal
concentration (25) or in finding any relation between higher doses and
the intensity of intrathyroidal autoimmune response (23). On the other
hand, thyroxine itself, which must be added to avoid hypothyroidism
when high doses of ATD are used, could act as an immunomodulator agent
(8, 12, 26).
In the present work, up to 63% of GD hyperthyroid patients relapsed
after 18 months of ATD treatment, and no difference in relapse rate
could be observed between the patients who received high doses of
carbimazole plus thyroxine and those who received lower doses. These
results differ from what was reported in 1983 by Romaldini (23), who
observed a difference of 33% on the remission rate between patients
treated with high or low doses of methimazole or propylthiouracil and
more recently, by Hashizume (8). In this last work, thyroxine was used
vs. placebo, first in combination with methimazole (12 m),
and afterwards alone for a 3-yr period, obtaining a very low rate of
relapse with the thyroxine treatment (1.7% vs. 35%). In
contrast, our work and that of several others (4, 14, 15, 16, 27, 28, 29), did
not obtain such differences in recurrence rate. These different
successes in achieving disease remission could be related to genetic,
geographic, or dietary differences in different populations (2, 29).
In our study, the only differences between groups at baseline were the
frequency of antimicrosomal Ab and the reported duration of
symptomatology, but these parameters did not differ between patients
who relapsed compared with those who did not, suggesting their limited
importance in the final results.
It is accepted that thyroid-stimulating Ab (TSAb) causes the
hyperthyroidism of GD, although etiological factors that induce
production of this Ab are unknown. Many studies have assessed the
effect of treatment of GD on levels of TSAb and have correlated these
levels with control of hyperthyroidism and its relapse rate. A
meta-analysis evaluation of more than 1500 patients (30) concluded that
undetectable TSH-receptors Ab at the end of ATD therapy reduces the
risk of relapse, although 25% of Ab-positive patients remained in
remission, and 25% of the Ab-negative patients relapsed. The reduced
number of our patients who presented positive TBII at the end of
treatment do not allow us to make any comments about this topic.
Some patients who were treated with combination therapy received
thyroxine to maintain an undetectable TSH level, to inhibit the release
of thyroid antigens, and, thereby, to modify the immunoresponse and the
GD evolution. In our patients, undetectable TSH after treatment was the
only independent variable to predict relapse. These results are in
agreement with those of McIver and Tamai (4, 16) who neither achieved a
higher remission rate in patients with undetectable TSH levels after
ATD therapy nor found any effect on their TBII levels.
Some clinicians (2), but not others (10), link the failure to decrease
TBII titters or thyroid gland size during ATD therapy to a high degree
of GD hyperthyroidism persistence or recurrence. In our study, although
patients who relapsed had larger goiters at baseline and at the end of
treatment, undetectable TSH level was the only independent variable to
predict relapse.
Our results, in agreement with Goñi’s (27) and
Escobar-Morreale’s (28), indicate that in Spanish patients the use of
high doses of carbimazole with thyroxine offers no advantages in GD
hyperthyroidism treatment. Nevertheless, as Hershmann said in his
editorial (31), better studies are needed to determine whether
thyroxine treatment prevents recurrence of GD hyperthyroidism and to
discover if some variables, such as thyroid size and biochemical
severity of disease, might influence this recurrence.
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Acknowledgments
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We thank Gary Shivel for valuable assistance in language
revision.
Received August 6, 1996.
Revised March 5, 1997.
Accepted May 1, 1997.
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Top
Abstract
Introduction
