ArticlePDF Available

TSH-receptor autoimmunity in Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: A 5-year prospective randomized study

Authors:
Article

TSH-receptor autoimmunity in Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: A 5-year prospective randomized study

Abstract

Autoimmunity against the TSH receptor is a key pathogenic element in Graves' disease. The autoimmune aberration may be modified by therapy of the hyperthyroidism. To compare the effects of the common types of therapy for Graves' hyperthyroidism on TSH-receptor autoimmunity. Patients with newly diagnosed Graves' hyperthyroidism aged 20-55 years were randomized to medical therapy, thyroid surgery, or radioiodine therapy (radioiodine was only given to patients > or = 35 years of age). L-thyroxine (L-T4) was added to therapy as appropriate to keep patients euthyroid. Anti-thyroid drugs were withdrawn after 18 months of therapy. TSH-receptor antibodies (TRAb) in serum were measured before and for 5 years after the initiation of therapy. Medical therapy (n=48) and surgery (n=47) were followed by a gradual decrease in TRAb in serum, with the disappearance of TRAb in 70-80% of the patients after 18 months. Radioiodine therapy (n=36) led to a 1-year long worsening of autoimmunity against the TSH receptor, and the number of patients entering remission of TSH-receptor autoimmunity with the disappearance of TRAb from serum during the following years was considerably lower than with the other types of therapy. The majority of patients with Graves' disease gradually enter remission of TSH-receptor autoimmunity during medical or after surgical therapy, with no difference between the types of therapy. Remission of TSH-receptor autoimmunity after radioiodine therapy is less common.
CLINICAL STUDY
TSH-receptor autoimmunity in Graves’ disease after therapy
with anti-thyroid drugs, surgery, or radioiodine: a 5-year
prospective randomized study
Peter Laurberg, Go¨ran Wallin
1
, Leif Tallstedt
2
, Mirna Abraham-Nordling
1
,Go¨ran Lundell
3
and Ove Tørring
4
Department of Endocrinology and Internal Medicine, Aalborg Hospital, Aarhus University Hospital, DK-9000 Aalborg, Denmark,
1
Department of Molecular Institution of Surgery, Karolinska University Hospital, Stockholm, Sweden,
2
Department of Ophthalmology, Karolinska
Institutet, St Erik’s Eye Hospital, Stockholm, Sweden,
3
Radiumhemmet, Department of General Oncology, Karolinska University Hospital, Stockholm,
Sweden and
4
Department of Endocrinology and Internal Medicine and Institution of Clinical Research and Education, So¨dersjukhuset, Karolinska Institutet,
Stockholm, Sweden
(Correspondence should be addressed to P Laurberg; Email: peter.laurberg@rn.dk)
Abstract
Introduction: Autoimmunity against the TSH receptor is a key pathogenic element in Graves’ disease.
The autoimmune aberration may be modified by therapy of the hyperthyroidism.
Objective: To compare the effects of the common types of therapy for Graves’ hyperthyroidism on TSH-
receptor autoimmunity.
Methods: Patients with newly diagnosed Graves’ hyperthyroidism aged 20–55 years were randomized
to medical therapy, thyroid surgery, or radioiodine therapy (radioiodine was only given to patients
R35 years of age).
L-thyroxine (L-T
4
) was added to therapy as appropriate to keep patients euthyroid.
Anti-thyroid drugs were withdrawn after 18 months of therapy. TSH-receptor antibodies (TRAb) in
serum were measured before and for 5 years after the initiation of therapy.
Results: Medical therapy (nZ48) and surgery (nZ47) were followed by a gradual decrease in TRAb in
serum, with the disappearance of TRAb in 70–80% of the patients after 18 months. Radioiodine
therapy (nZ36) led to a 1-year long worsening of autoimmunity against the TSH receptor, and the
number of patients entering remission of TSH-receptor autoimmunity with the disappearance of TRAb
from serum during the following years was considerably lower than with the other types of therapy.
Conclusion: The majority of patients with Graves’ disease gradually enter remission of TSH-receptor
autoimmunity during medical or after surgical therapy, with no difference between the types of
therapy. Remission of TSH-receptor autoimmunity after radioiodine therapy is less common.
European Journal of Endocrinology 158 69–75
Introduction
Graves’ disease is a common autoimmune disorder with
various clinical manifestations. The cause for the most
prevalent abnormality, hyperthyroidism, is thyrotrophin
(TSH)-receptor-stimulating autoantibodies and such
antibodies are also believed to cause the diffuse, hyper-
vascular goiter observed in many patients. The exact
mechanism leading to Graves orbitopathy is not firmly
established but there is a correlation between disease
activity and TSH-receptor antibodies (TRAb) in blood
(1, 2). Patients with the more uncommon mani-
festations, pretibial myxedema and thyroid acropachy,
are normally characterized by severe general disease with
high circulating levels of TRAb (3). TRAb in serum can
be measured by their binding to the TSH receptor in vitro,
or by more cumbersome biological methods. The
performance of assays differ considerably (4, 5),but
apart from such technical limitations, TRAb in serum is
an indicator of the overall autoimmune abnormality in
Graves’ disease (6).
Like other autoimmune diseases, Graves’ disease is
most likely caused by a combination of genetic and
environmental factors that may also determine the long-
term prognosis of the disorder. Over time, the disease
may uctuate in activity and occasionally patients may
spontaneously become euthyroid (7). In addition to such
a variation, it is well established that the therapy of
hyperthyroidism may influence disease activity (6).
During prolonged follow-up, TRAb tend to disappear
from serum after all types of therapy for hyperthyroidism
(8–10).
To obtain more detailed information on the effects of
hyperthyroidism therapy on the autoimmune abnorm-
ality of Graves’ disease, we followed TRAb in serum for a
5-year period in a prospective randomized study
comparing the three common therapies, antithyroid
drugs, subtotal thyroidectomy, and radioiodine therapy.
European Journal of Endocrinology (2008) 158 69–75 ISSN 0804-4643
q 2008 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-07-0450
Online version via www.eje-online.org
Patients and methods
All patients between 20 and 55 years of age, who were
referred to the involved units in Sweden for untreated
Graves’ hyperthyroidism and with no previous thyroid
disease, were evaluated for inclusion in the study as
described in detail previously (11, 12). All 179 patients
who agreed to enter the study were included and
stratified into two groups according to age. Patients,
20–34 years old (nZ60), were randomly assigned to
treatment with antithyroid drugs plus
L-thyroxine (L-T
4
;
medical therapy) or subtotal thyroidectomy followed by
L-T
4
(surgery). Patients, 35–55 years old (nZ119),
received medical therapy, surgery, or radioiodine.
Radioiodine was not used by the involved departments
for therapy of Graves’ disease in patients below 35 years
of age. Randomization was performed by assigning each
patient a treatment group consecutively using two lists,
one for each age group. On the list, each treatment
group occurred in a random order but was balanced to
equalize the size of the treatment groups. The lists were
unavailable to the clinicians throughout the study, and
randomization was performed over the phone.
As described previously in the report on clinical
outcomes of therapy (12), 71 patients were randomized
to receive medical therapy. Mean (
S.D.) tri-iodothyronine
(T
3
) was 6.3 (2.0) nmol/l, T
4
239 (72) nmol/l, and free
T
4
59 (26) pmol/l in young patients (nZ30); mean (S.D.)
T
3
was 5.4 (1.7) nmol/l, T
4
224 (55) nmol/l, and free T
4
57 (17) pmol/l in old patients (nZ41). Medication was
given as 10 mg methimazole, four times daily, for 18
months. Three to five weeks after start,
L-T
4
was added
in doses of 0.1–0.3 mg per day to keep a normal serum
T
3
and a slightly suppressed serum TSH. L-T
4
was
withdrawn simultaneously with methimazole after 18
months. In the case of methimazole intolerance therapy
was continued with propylthiouracil. After 48 months
of follow-up, the overall risk of reoccurrence of
hyperthyroidism in the medically treated young and
old adults was calculated to be 42 and 34% respectively,
as published previously (12). None of the patients
staying euthyroid were in need of
L-T
4
therapy. Thus,
more than one half of the medically treated patients had
a prolonged period of euthyroidism without any
medication after the halt of therapy.
Patients randomized to surgery (nZ67) were pre-
treated with at least 40 mg propranolol three to four
times daily, or an equivalent dose of metoprolol. Seven
patients received Lugol’s solution in addition. The
procedure was subtotal thyroidectomy leaving w 1gor
less of thyroid tissue in each lobe.
L-T
4
therapy was
started around day 4 after surgery to avoid hypothyr-
oidism. At the time of inclusion, mean (
S.D.) serum T
3
was 5.6 (1.8) nmol/l, T
4
was 221 (46) nmol/l, and
free T
4
was 60 (24) pmol/l in young patients (nZ30),
while in old patients T
3
was 5.4 (1.9) nmol/l, T
4
224
(55) nmol/l, and free T
4
57 (25) pmol/l. After 48
months of follow-up, the overall risk of reoccurrence of
hyperthyroidism in the surgically treated young and old
patients was calculated to be 3 and 8% respectively (12).
All the patients remaining euthyroid received
L-T
4
substitution therapy.
Forty-one patients were randomized to
131
iodine
therapy. This was given as a single oral dose calculated
to deliver 120 Gray units to the thyroid.
L-T
4
therapy was
initiated as soon as serum TSH was elevated and/or when
serum free T
4
,T
4
,orT
3
were low. At the time of inclusion,
mean (
S.D.) serum T
3
was 5.3 (1.7) nmol/l, T
4
was 221
(57) nmol/l, and free T
4
was 55 (19) pmol/l. Serum
thyroid hormone values were not significantly different
between the three treatment groups before therapy.
Neither was there any difference in sex distribution or
the number of smokers between groups (12).After48
months of follow-up, the risk of reoccurrence of
hyperthyroidism was calculated to be 21% after
131
iodine
therapy (12). All patients treated with radioiodine
endedupbeingon
L-T
4
substitution therapy for
hypothyroidism (12).
All TSH receptor antibody (TRAb) measurements were
performed by a radioreceptor assay kit provided by RSR
Ltd, Cardiff, UK. In this method,
125
I-labeled bovine TSH
compete with TRAb in serum samples to bind to purified
porcine TSH receptors, followed by polyethylene glycol
precipitation (13). After the completion of our study, new
generations of TRAb assays have been developed (14, 15),
and it has been shown that a minor subset of sera from
patients with Graves’ disease are falsely negative using the
assay employed in our study (15). For the present
calculations and presentation of results, we included
only patients who were TRAb-positive at the time of
inclusion in the study and before therapy.
Among the 179 patients originally included in the
study (11, 12), results of TRAb measurements before
therapy were not available in five, and in another 29
patients the initial TRAb results were within the normal
reference range for the assay (!10% displacement of
125
I-labeled TSH). Among the remaining 145 patients,
one left the area before 12 months and one left the study
with no further samples available because of cancer
therapy. Both had been assigned to the medical therapy
group. One patient randomized to surgery started
treatment with medication and was not operated
upon, one rejected radioiodine therapy, one patient
randomized to medical therapy did not comply with
treatment and control, and two developed intolerance to
both methimazole and propylthiouracil and underwent
surgery. Further, three patients had a reoccurrence of
hyperthyroidism after surgery and subsequently
received radioiodine (after 3, 13, and 18 months), and
four patients did not become stably euthyroid on
medication and underwent surgery after 6, 10, 11,
and 17 months of therapy. They were all excluded from
the general analysis. This analysis included 48 patients
(F/M, 41/7) receiving medical therapy, 47 (40/7)
undergoing surgery, and 36 (31/5) treated with radio-
iodine. The number of patients in the three groups
70
P Laurberg and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158
www.eje-online.org
(medical/surgical/radioiodine) still included in the
analyses is as follows: after 1 year, 48/47/36; after 2
years, 43/44/35; after 3 years, 26/40/35; after 4 years,
24/38/34; and after 5 years, 24/38/34.
Serum T
3
,T
4
, and free T
4
were measured as described
previously (11). The reference ranges were: T
3
,
1.1–2.5 nmol/l; T
4
,75150nmol/l;andfreeT
4
,
9–21 pmol/l.
Patients were included after informed consent, and
the protocol was approved according to Swedish ethics
regulations.
Calculations and statistical analyses
In this prolonged multicenter study, it was not possible
to arrange control and blood sampling on precise dates
for the entire 5-year period, and control had to some
degree to be adapted to the individual patient’s need
(11, 12). For the evaluation of TRAb variation after
therapy we constructed curves for each patient from the
available results of measurements, and the TRAb value
at the specific time point indicated was read and used for
calculations. The number of TRAb results from each
patient available during different periods of the follow-
up were as follows: 1 year, 3.7G1.3 (mean,
S.D.); 2
years, 2.4G1.3; 3 years, 1.2G0.8; 4 years, 0.8G0.5;
and 5 years, 1.1G 0.6. As we found no difference in the
TRAb response between young and old patients treated
with medication or surgery, the age groups were
combined.
Raw data were entered into a SPSS database, and data
handling and statistical analyses were performed using
SPSS v. 13.0 software (SPSS Inc., Chicago, IL, USA). For
comparisons of groups, we used non-parametric tests
(Mann–Whitney or Kruskal–Wallis test, depending on
the number of strata) and c
2
-test (comparison of
percentages). The level of significance was set at 5%.
Results
The levels of TRAb were similar in the three groups of
patients before therapy (Fig. 1). During medical therapy
and after surgery, the average TRAb in serum gradually
decreased to reach the upper level of the normal
reference interval for the assay after about 1 year. The
TRAb values in these two groups were not significantly
different (PO0.05) before therapy and after 6, 12, 24,
36, 48, and 60 months.
The therapy with radioiodine induced a different
pattern (Fig. 1). A considerable increase in TRAb was
observed immediately after therapy with maximal value
at the first time point of evaluation (3 months). This
peak was followed by a gradual fall, and after about 1
year the average TRAb value had returned to the
pretreatment level. Subsequently, TRAb values contin-
ued to decrease, but slowly, and average values were
well above the normal reference throughout the 5 years
of follow-up. When compared, TRAb values in the three
therapy groups were not different before therapy
(PZ0.60), but significantly different after 6, 12, 24,
36, 48, and 60 months (P!0.003).
The frequency of achieving a state where TRAb in
serum had become negative (!10%) after various time
periods is shown in Fig. 2. Corresponding to the
variation in the average TRAb values depicted in
Fig. 1, the patients became TRAb-negative to a lesser
degree and much later after radioiodine therapy than
during medical or after surgical therapy.
The favorable outcome with regard to disappearance
of TRAb after medical and surgical therapy might have
been facilitated by the exclusion of patients with early
reoccurrence of hyperthyroidism after surgery (nZ3)
and patients who did not respond adequately to
antithyroid drug therapy (nZ4). The available TRAb
values from the four patients who were excluded from
the medication group are depicted in Fig. 3. All had high
levels of TRAb before therapy and no or little decrease in
TRAb values during the period of medication.
Similarly, patients who did not follow the protocol
because they had reoccurrence of hyperthyroidism at
some point after stopping the medication were excluded
from the study from the time they left the protocol. This
is illustrated in Fig. 4, showing the average TRAb values
in the medication group, and the time of individual
reoccurrence of hyperthyroidism. A total of 16 patients
experienced reoccurrence of hyperthyroidism after
Figure 1 Variations in TSH-receptor antibodies in serum after
randomly assigning patients with Graves’ hyperthyroidism to
radioiodine (nZ36; radioiodine was only given to patients being
R35 years of age), surgery (nZ47), or medical therapy (nZ48). In
all groups, patients were kept euthyroid by the addition of L-T
4
to
therapy as appropriate. Medical therapy was given for 18 months.
The values for the patients who needed a treatment other than the
randomized are omitted beyond the time the change occurred.
Values are meanG
S.E.M. The upper normal reference for the TRAb
assay was 10% as indicated by the stapled line. Values before
therapy were not different between groups. After therapy, all values
were significantly higher for the radioiodine group when compared
with values for the medical or surgical therapy groups (P!0.01).
Therapy and TSH-receptor antibodies
71EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158
www.eje-online.org
medication had been stopped at 18 months. An
associated increase in TRAb (measured before or shortly
after new therapy) was observed in 14 patients,
whereas TRAb was continuously present in one patient
with early hyperthyroidism, and not available around
the time of new hyperthyroidism in one patient.
Individual TRAb values before and at the time of
reoccurrence of hyperthyroidism are given in the legend
to Fig. 4.
Among the patients who responded to medical
therapy, TRAb levels decreased both in those who
stayed euthyroid and those experiencing new hyperthyr-
oidism after stopping medication. Average levels were
significantly higher at 12 and 18 months of therapy,
and more patients were TRAb-positive at 18 months
in the group that subsequently developed hyperthyr-
oidism (Fig. 5).
Discussion
We monitored variations in TRAb in serum for 5 years
after the three common types of therapy of patients with
hyperthyroidism caused by Graves’ disease. A clear
difference in the early TRAb response to therapy was
observed, with a surge of about one year duration in
TRAb after radioiodine therapy. In contrast, TRAb levels
decreased in parallel during the rst year in patients
becoming euthyroid from medication or surgery. After
one year, patients continued to enter remission of TSH-
receptor autoimmunity with the disappearance of TRAb
from serum in all therapy groups, but the frequency of
such remission was lower in the radioiodine group.
Figure 2 Fractions of patients becoming TRAb-negative (value
below 10%) after radioiodine (nZ36; radioiodine was only given to
patients R35 years of age), surgery (nZ47), or medical therapy
(nZ48). Dots indicate values for the point of time indicated. Lines
are trend lines. Medical therapy was given for 18 months. The
values for the patients who needed a treatment other than the
randomized are omitted beyond the time the change occurred.
Values are not different between medication and surgery, but lower
after radioiodine (P!0.01, at time points 6, 12, 24, 36, 48, and 60
months). See legend to Fig. 1 for further details.
Figure 3 Course of TRAb in serum in four patients who did not
respond adequately to medical therapy. They represent 6% out of
the 68 patients initially allocated to medical therapy. The patients
did not become euthyroid despite the increase in doses up to 60 mg
methimazole or 600 mg propylthiouracil per day. All patients
subsequently underwent subtotal thyroidectomy as indicated by the
arrows. The patient who was thyroidectomized after 6 months in
addition received radioiodine after 18 months.
Figure 4 The average TRAb values in the group receiving medical
therapy for 18 months (nZ48). Arrows indicate the points of time at
which 16 patients experienced a reoccurrence of hyperthyroidism.
Eight were subsequently treated with radioiodine and the other eight
underwent surgery, and they all left the study at the time of new
therapy. The individual TRAb values measured in the patients with
the reoccurrence of hyperthyroidism were (listed from early to late
occurrence of hyperthyroidism), before new hyperthyroidism
15.2%, at the time of new hyperthyroidism 40.1%; 17.1, 30.4; 12.2,
45.0; !10.0, 11.8; 17.4, 17.4; 14.1, 23.9; !10.0, 20.3; !10.0,
not measured; !10.0, 25.6; !10.0, 57.3; 12.8, 19.9; !10.0, 46.8;
!10.0, 15.2; !10.0, 23.6; !10.0, 18.8; !10.0, 24.0. Another eight
patients were lost to follow-up and left: two between 18 and 24
months, three after the 24-month visit, and the remaining after visits
at 27, 30, and 33 months.
72 P Laurberg and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158
www.eje-online.org
It is well established that radioiodine therapy induces
a transient increase in TRAb in serum (16, 17),
presumably caused by the release of thyroid antigens,
but this response has not previously been compared in a
randomized study with the response to both surgery
and medication. The results indicate that the auto-
immune activity in Graves’ disease is much higher
during the initial period after radioiodine therapy than
after other types of therapy, and also that fewer patients
treated with radioiodine enter remission of TSH-
receptor autoimmunity with the disappearance of
TRAb from serum during prolonged observation.
Patients treated with surgery or medication showed a
gradual fall in TRAb in serum, and after one year, 50–
60% of the patients had entered remission of TSH-
receptor autoimmunity with the disappearance of TRAb
from serum. The mechanism behind such a remission
during therapy has not been fully clarified. As discussed
previously (18), the hyperthyroid state may somehow
perpetuate the autoimmune abnormality. When
patients become euthyroid after medication or surgery
the majority will gradually enter remission of TSH-
receptor autoimmunity. However, other possible
mechanisms for remission have been proposed (19).
A minority of patients with Graves’ disease do not
enter remission of TSH-receptor autoimmunity after
medication or surgery. In the present study, three
patients had reoccurrence of hyperthyroidism after
surgery and four patients did not respond properly
to medication and subsequently underwent surgery.
As shown in Fig. 3, all four patients responding
insufficiently to medication had high levels of TRAb
with little tendency to enter remission of TSH-receptor
autoimmunity during medical therapy. The exclusion of
these patients from follow-up made the results after
medication and surgery appear more favorable.
However, this cannot explain the observed difference
in TRAb results after the various therapies. The 5–10%
of patients with the most severe form of Graves’ disease
may have problems with all types of therapy (20).
Even when patients responded well to medication or
surgery, the disappearance of TRAb in serum came
gradually over a considerable period of time. It is
important to recognize that successful thyroid surgery
in Graves’ disease will immediatelycure the hyperthyroid
state, but normalization of the autoimmune abnorm-
ality comes much later. Thus, when thyroidectomy is
advocated in difcult-to-treat pregnant women with
Graves’ hyperthyroidism, this may be an effective
treatment of the mother, but it may increase the risk
of successive fetal hyperthyroidism when compared
with the situation under antithyroid drug therapy.
TSH-receptor-stimulating antibodies produced in the
mother will pass the placenta, and their stimulation of
the fetal thyroid will no longer be opposed by
antithyroid drugs (21).
The surge in TRAb during the first year after
radioiodine therapy is associated with a risk of
development or worsening of Graves’ orbitopathy (22).
In the present study, this risk was nearly entirely
confined to patients with the highest levels of serum T
3
(11). In Graves’ disease, disproportionately high serum
T
3
is a sign of severe thyroid hyperactivity (23) and the
findings further illustrate the problems that may be
experienced with patients having the most severe form
of Graves’ disease.
It has been shown that a period of pretreatment with
antithyroid drugs may diminish the TRAb surge after
radioiodine (24, 25) possibly because the patients have
entered partial remission of TSH-receptor autoimmunity
(25). Whether this may reduce the risk for worsening of
orbitopathy after radioiodine therapy remains to be
proven. A study performed in Hong Kong showed no
effect of antithyroid drugs given after radioiodine (26),
and in another study the majority of patients were
TRAb-positive one year after radioiodine, irrespective
of pretreatment with methimazole (25). It has been
shown that the risk for orbitopathy is much lower if
radioiodine is given with a course of prednisolone
therapy (27).
A pertinent question remains of whether the
persistence in many patients of TRAb, even years after
radioiodine therapy, indicates that the chance of long-
term improvement of orbitopathy is lower after radio-
iodine than after other types of therapy. Another
consideration is the risk of radioiodine treatment of fetal
hyperthyroidism during a later pregnancy in young
women (21). Radioiodine is often recommended to
young women to overcome any future problems with
Figure 5 The average TRAb variation in medically treated patients
who stayed euthyroid after stop of medical therapy (nZ30), and
those who became hyperthyroid again (nZ16). Two patients who
stayed euthyroid but with !6 months of follow-up after stop of
medication were not included. TRAb values in the two groups of
patients were not significantly different during the time period 0–9
months, but thereafter TRAb was significantly higher in the group
who developed hyperthyroidism (P!0.05) as indicated by*.
Therapy and TSH-receptor antibodies
73EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158
www.eje-online.org
Graves’ disease during pregnancy. However, even if the
woman is made hypothyroid by radioiodine and
subsequently euthyroid by
L-T
4
administration, TRAb
may remain high for years. Thus, there is a need to
measure TRAb in early pregnancy in such women (21)
and to follow the fetus carefully for hyperthyroidism, if
TRAb is still present. In the present study, radioiodine
was not given to patients below 35 years of age. There is
no indication that the TRAb response to radioiodine
should be age-dependent, but this possibility should be
studied in more detail.
Medical therapy led to a fall in TRAb similar to the fall
after surgery. However, this only lasted for the 18-month
period the medication was given. After stopping
medication, some of the patients had a reactivation
of the autoimmune abnormality with an increase in or
reappearance of TRAb in serum and with the reoccur-
rence ofhyperthyroidism. The riskof newhyperthyroidism
was considerably higher in patients who were TRAb-
positive at the end of medical therapy, but the initial TRAb
values and the fall in TRAb during therapy overlapped
between patients who became hyperthyroid and those
who remained euthyroid. In patients who do not accept
the risk of new hyperthyroidism after the stop of
medication, prolonged medical therapy may be useful
(28–31). This should be balanced against the risk of drug
side effects (32). More studies are needed on the optimal
protocol for medical therapy of Graves’ hyperthyroidism,
and development of antithyroid drugs with less side
effects would make prolonged medical therapy more
attractive (20).
If sensitive bioassays are used, all patients with
hyperthyroidism caused by Graves’ disease have thyroid-
stimulating antibodies in serum (33). Assays used in
clinical routine differ considerably in their ability to detect
such antibodies (4, 5), but recent generations of assays
show high sensitivity and specificity (14, 15).Inthe
present study, TRAb was measured using a radioreceptor
assay that was able to detect TRAb in 83% of the
untreated patients. All studies using in vitro assays for
detecting TRAb in patients with Graves disease have
found a subgroup of patients being TRAb-negative. In
general, TRAb-negative patients tend to have a milder
disease (34, 35). As the aim of the present study was to
follow the variations in TRAb after therapy, we excluded
patients that were TRAb-negative before therapy.
Conclusion
We describe in detail the course of TSH-receptor
autoimmunity after the three common types of therapy
for Graves’ hyperthyroidism. Medical therapy and
subtotal thyroidectomy were followed by a gradual
and parallel remission of TSH-receptor autoimmunity,
with the disappearance of TRAb from serum in 70–80%
of the patients after 18 months. After stopping therapy,
around 40% of medically treated patients experienced
a reactivation of TSH-receptor autoimmunity and
became hyperthyroid again. Radioiodine therapy led
to a year-long worsening of autoimmunity against the
TSH receptor, and the number of patients entering
remission of TSH-receptor autoimmunity with disap-
pearance of TRAb from serum during the following
years was considerably lower than with the other types
of therapy.
Acknowledgements
PL: Research Support by BRAHMS Diagnostica, Berlin,
Germany.
References
1 Gerding MN, van der Meer JW, Broenink M, Bakker O,
Wiersinga WM & Prummel MF. Association of thyrotrophin receptor
antibodies with the clinical features of Graves’ ophthalmopathy.
Clinical Endocrinology 2000 52 267–271.
2 Eckstein AK, Plicht M, Lax H, Hirche H, Quadbeck B, Mann K,
Steuhl KP, Esser J & Morgenthaler NG. Clinical results of anti-
inflammatory therapy in Graves’ ophthalmopathy and association
with thyroidal autoantibodies. Clinical Endocrinology 2004 61
612–618.
3 Fatourechi V. Pretibial myxedema: pathophysiology and treatment
options. American Journal of Clinical Dermatology 2005 6 295–309.
4 Pedersen IB, Knudsen N, Perrild H, Ovesen L & Laurberg P.
TSH-receptor antibody measurement for differentiation of hyper-
thyroidism into Graves’ disease and multinodular toxic goitre: a
comparison of two competitive binding assays. Clinical Endocrinology
2001 55 381–390.
5 Preissner CM, Wolhuter PJ, Sistrunk JW, Homburger HA &
Morris JC, III. Comparison of thyrotropin-receptor antibodies
measured by four commercially available methods with a bioassay
that uses Fisher rat thyroid cells. Clinical Chemistry 2003 49
1402–1404.
6 Davies TF, Ando T, Lin RY, Tomer Y & Latif R. Thyrotropin
receptor-associated diseases: from adenomata to Graves disease.
Journal of Clinical Investigation 2005 115 1972–1983.
7 Codaccioni JL, Orgiazzi J, Blanc P, Pugeat M, Roulier R & Carayon P.
Lasting remissions in patients treated for Graves’ hyperthyroidism
with propranolol alone: a pattern of spontaneous evolution of
the disease. Journal of Clinical Endocrinology and Metabolism 1988
67 656–662.
8 Pinchera A, Liberti P, Martino E, Fenzi GF, Grasso L, Rovis L,
Baschieri L & Doria G. Effects of antithyroid therapy on the long-
acting thyroid stimulator and the antithyroglobulin antibodies.
Journal of Clinical Endocrinology and Metabolism 1969 29 231–238.
9 Aizawa Y, Yoshida K, Kaise N, Kaise K, Fukazawa H, Kiso Y, Mori K,
Sayama N, Kikuchi K & Abe K. Long-term effects of radioiodine
on thyrotrophin receptor antibodies in Graves’ disease. Clinical
Endocrinology 1995 42 517–522.
10 Takamura Y, Nakano K, Uruno T, Ito Y, Miya A, Kobayashi K,
Yokozawa T, Matsuzuka F, Kuma K & Miyauchi A. Changes in
serum TSH receptor antibody (TRAb) values in patients with
Graves’ disease after total or subtotal thyroidectomy. Endocrine
Journal 2003 50 595–601.
11 Tallstedt L, Lundell G, Torring O, Wallin G, Ljunggren JG,
Blomgren H & Taube A. Occurrence of ophthalmopathy after
treatment for Graves’ hyperthyroidism. The Thyroid Study Group.
New England Journal of Medicine 1992 25 1733–1738.
12 Torring O, Tallstedt L, Wallin G, Lundell G, Ljunggren JG, Taube A,
Saaf M & Hamberger B. Graves’ hyperthyroidism: treatment with
74 P Laurberg and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158
www.eje-online.org
antithyroid drugs, surgery, or radioiodine a prospective,
randomized study. Thyroid Study Group. Journal of Clinical
Endocrinology and Metabolism 1996 81 2986–2993.
13 Southgate K, Creagh F, Teece M, Kingswood C & Rees Smith B. A
receptor assay for the measurement of TSH receptor antibodies in
unextracted serum. Clinical Endocrinology 1984 20 539–548.
14 Morgenthaler NG, Nagata A, Katayama S, Bergmann A &
Iitaka M. Detection of low titre TBII in patients with Graves’
disease using recombinant human TSH receptor. Clinical Endo-
crinology 2002 57 193–198.
15 Smith BR, Bolton J, Young S, Collyer A, Weeden A, Bradbury J,
Weightman D, Perros P, Sanders J & Furmaniak J. A new assay for
thyrotropin receptor autoantibodies. Thyroid 2004 14 830–835.
16 Atkinson S, McGregor AM, Kendall-Taylor P, Peterson MM &
Smith BR. Effect of radioiodine on stimulatory activity of Graves’
immunoglobulins. Clinical Endocrinology 1982 16 537–543.
17 Teng CS, Yeung RT, Khoo RK & Alagaratnam TT. A prospective
study of the changes in thyrotropin binding inhibitory immuno-
globulins in Graves’ disease treated by subtotal thyroidectomy or
radioactive iodine. Journal of Clinical Endocrinology and Metabolism
1980 50 1005–1010.
18 Laurberg P. Remission of Graves’ disease during anti-thyroid drug
therapy. Time to reconsider the mechanism? European Journal of
Endocrinology 2006 155 783–786.
19 McGregor AM, Petersen MM, McLachlan SM, Rooke P, Smith BR &
Hall R. Carbimazole and the autoimmune response in Graves’
disease. New England Journal of Medicine 1980 7 302–307.
20 Laurberg P, Andersen S & Karmisholt J. Anti-thyroid drug therapy
of Graves’ hyperthyroidism: realistic goals and focus on evidence.
Expert Review of Endocrinology and Metabolism 2006 1 91–102.
21 Laurberg P, Nygaard B, Glinoer D, Grussendorf M & Orgiazzi J.
Guidelines for TSH-receptor antibody measurements in preg-
nancy: results of an evidence-based symposium organized by the
European Thyroid Association. European Journal of Endocrinology
1998 139 584–586.
22 Wiersinga WM & Bartalena L. Epidemiology and prevention of
Graves’ ophthalmopathy. Thyroid 2002 12 855–860.
23 Laurberg P, Vestergaard H, Nielsen S, Christensen SE, Seefeldt T,
Helleberg K & Pedersen KM. Sources of circulating T
3
in
hyperthyroidism estimated after blocking of type 1 and type 2
iodothyronine deiodinases. Journal of Clinical Endocrinology and
Metabolism 2007 92 2149–2156.
24 Gamstedt A, Wadman B & Karlsson A. Methimazole, but not
betamethasone, prevents
131
I treatment-induced rises in thyrotropin
receptor autoantibodies in hyperthyroid Graves’ disease. Journal of
Clinical Endocrinology and Metabolism 1986 62 773–777.
25 Andrade VA, Gross JL & Maia AL. Serum thyrotropin-receptor
autoantibodies levels after
131
I therapy in Graves’ patients: effect
of pretreatment with methimazole evaluated by a prospective,
randomized study. European Journal of Endocrinology 2004 151
467–474.
26 Kung AW, Yau CC & Cheng A. The incidence of ophthalmopathy
after radioiodine therapy for Graves’ disease: prognostic factors
and the role of methimazole. Journal of Clinical Endocrinology and
Metabolism 1994 79 542–546.
27 Bartalena L, Marcocci C, Bogazzi F, Manetti L, Tanda ML,
Dell’Unto E, Bruno-Bossio G, Nardi M, Bartolomei MP, Lepri A,
Rossi G, Martino E & Pinchera A. Relation between therapy for
hyperthyroidism and the course of Graves’ ophthalmopathy. New
England Journal of Medicine 1998 8 73–78.
28 Shizume K. Long term antithyroid drug therapy for intractable
cases of Graves’ disease. Endocrinologia Japonica 1978 25
377–379.
29 Slingerland DW & Burrows BA. Long-term antithyroid treatment
in hyperthyroidism. Journal of the American Medical Association
1979 30 2408–2410.
30 Lippe BM, Landaw EM & Kaplan SA. Hyperthyroidism in children
treated with long term medical therapy: twenty-five percent
remission every two years. Journal of Clinical Endocrinology and
Metabolism 1987 64 1241–1245.
31 Azizi F, Ataie L, Hedayati M, Mehrabi Y & Sheikholeslami F. Effect of
long-term continuous methimazole treatment of hyperthyroidism:
comparison with radioiodine. European Journal of Endocrinology
2005 152 695–701.
32 Cooper DS. Antithyroid drugs. New England Journal of Medicine
2005 3 905–917.
33 Sato K, Yamazaki K, Yamada E, Kanaji Y, Miura M & Obara T.
Immunoglobulins of untreated Graves’ patients with or without
thyrotropin receptor antibody (determined by porcine thyrocytes)
universally elicit potent thyroid hormone-releasing activity in
cultured human thyroid follicles. Thyroid 1999 9 979–988.
34 Mukuta T, Tamai H, Oshima A, Morita T, Matsubayashi S,
Fukata S & Kuma K. Immunological findings and thyroid function
of untreated Graves’ disease patients with undetectable TSH-
binding inhibitor immunoglobulin. Clinical Endocrinology 1994 40
215–219.
35 Kawai K, Tamai H, Matsubayashi S, Mukuta T, Morita T, Kubo C &
Kuma K. A study of untreated Graves’ patients with undetectable
TSH binding inhibitor immunoglobulins and the effect of anti-
thyroid drugs. Clinical Endocrinology 1995 43 551–556.
Received 21 September 2007
Accepted 8 October 2007
Therapy and TSH-receptor antibodies
75EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158
www.eje-online.org
... Patients treated with surgery (thyroidectomy) or medication show a gradual decrease in serum TRAb level, and after 1 year, 50% to 60% of patients enter remission of TSH receptor autoimmunity accompanied by the disappearance of TRAb from serum. 26 28 29 Similarly, untreated TED improves spontaneously over time in most patients (described as 'Rundle's curve'). 30 31 Moreover, studies report that TRAb levels associated with TED also decrease over time. ...
Article
Full-text available
Objectives The clinical course of thyroid eye disease (TED) is heterogeneous and predicting patients who may develop the severe sequelae of the disease is difficult. In this study, we evaluated the longitudinal association between changes in serum thyroid-stimulating hormone (TSH) receptor antibody (TRAb) levels and course of disease activity and severity over time. Design This was a multicentre, prospective, observational study. Setting Fifteen tertiary care oculoplastic service centres in Korea. Participants Seventy-six patients with newly diagnosed TED were included and followed up for 12 months. Methods We evaluated clinical characteristics and serum TRAb levels at baseline, 6 and 12 months of TED diagnosis. Additionally, we analysed longitudinal associations between the serum TRAb levels and clinical activity score (CAS), no signs or symptoms, only signs, soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement, sight loss (NOSPECS) score and proptosis. Results Thyroid-stimulating immunoglobulin (TSI) and TSH-binding inhibitory immunoglobulin (TBII) levels decreased during the 1-year follow-up, whereas disease activity measured using CAS decreased mainly in the first 6 months. Disease severity measured using NOSPECS score and proptosis remained unchanged. Moreover, inter-person differences in TBII levels were associated with CAS, NOSPECS score and proptosis over time, whereas inter-person differences in TSI levels were associated with NOSPECS score. Subgroup analysis of patients with a baseline CAS≥4 demonstrated that within-person changes in TSI levels affected the CAS and NOSPECS score. Conclusions Follow-up measurement of serum TSI and TBII levels may help evaluate TED prognosis and enable accurate clinical decision-making.
... Previous studies showed that more severe initial serum thyroid hormone levels correlated with the greater extent of weight gain in postthyroidectomy patients [13,20]. In addition, higher serum TRAb levels had been consistently shown to be higher in post-RAI treatment when compared with other treatments [21] while long-term ATD treatment could lower serum TRAb levels [22]. Recent evidence from clinical and experimental data showed that thyrotropin receptor signaling enhanced adipogenesis and involved in the transformation from brown fat to white fat [23]. ...
Article
Full-text available
Background: Weight gain post-radioiodine (RAI) treatment is observed in patients with hyperthyroid Graves’ disease. Previous studies, mostly in Caucasian patients, demonstrated excessive weight gain averaging 5-7 kilograms from initial presentation. Aim: The aim of this study was to determine the extent and risk factors of weight gain in Thai patients with RAI-treated Graves’ disease. Methods: This was a 5-year retrospective study of patients with hyperthyroid Graves’ disease who received RAI treatment during 2016-2020. The proportion and associated risk factors of weight gain ≥ 5% in patients who was followed for at least 3 months when compared with weight at RAI administration were analyzed. Results: There were 347 patients with Graves’ disease (females 81.0%, mean age 38.8±12.1 years, BMI 23.3±4.0 kg/m²) who were treated with RAI. Almost all RAI-treated patients (91.9%) eventually developed hypothyroidism. During the median follow-up period of 25 months, 73.1% of them had weight gain. The mean weight change was +2.5±4.9 kgs when compared with weight at the time RAI administration and +3.4±6.5 kgs when compared with recalled body weight before the onset of hyperthyroidism. The proportion of patient in the obesity class I (BMI 25.0-29.9 kg/m²) increased from 23.6% to 28.0% and obesity class II (BMI ≥ 30.0 kg/m²) increased from 5.2% to 8.9%. Duration of antithyroid drug treatment less than 6 months after the diagnosis of hyperthyroidism was the only factor associated with weight gain ≥ 5%. Conclusions: Weight gain post-RAI treatment was common, and a significant proportion of patients went on to develop obesity. Early intervention with weight management support should be employed in patients with less than 6 months of antithyroid drug treatment before RAI.
... Although we could not find evidence for preconceptional TRAb elevation as a predictive factor for fetal and neonatal autoimmune hyperthyroidism in our patient, cessation of ATDs in the mother was a non-negligible risk factor [4,5]. The notions of fetal tachycardia as from the 5 th month of pregnancy and the recurrence of early active fetal movements accounted for fetal or congenital hyperthyroidism [1,3]. ...
Article
Full-text available
Neonatal Grave’s disease is associated with maternal Grave or Basedow’s hyperthyroidism, which is a rare endocrinopathy in pregnant women. In this report, we present and discuss the case of an infant with congenital and neonatal hyperthyroidism with neurological manifestations. Such presentations are rare, with congenital onset and neurological signs not often at the front line, although tremor sometimes mentioned in the literature may be expected. However, repeated and persistent myoclonus is exceptional, and the certitude of complete resolution of abnormal movements, even with a well conducted treatment is not always guaranteed.
Chapter
Toxic diffuse goiter (Graves' disease) is more common in women, as in most autoimmune diseases, and is the most common cause of hyperthyroidism in young women (60–80%). The ratio of women to men is 10:1 [1]. Family history is found in close to 50% of patients [2].
Book
Full-text available
Prevención, diagnóstico y manejo de las complicaciones en pacientes oncológicos: un enfoque multidisciplinario
Article
Graves’ orbitopathy (GO) is an orbital autoimmune disorder and the main extrathyroidal manifestation of Graves’ disease, the most common cause of hyperthyroidism. GO affects about 30% of Graves’ patients, although fewer than 10% have severe forms requiring immunosuppressive treatments. Management of GO requires a multidisciplinary approach. Medical therapies for active moderate‐to‐severe forms of GO (traditionally, high‐dose glucocorticoids) often provide unsatisfactory results, and subsequently surgeries are often needed to cure residual manifestations. The aim of this review is to provide an updated overview of current concepts regarding epidemiology, pathogenesis, assessment, and treatment of GO, and to present emerging targeted therapies and therapeutic perspectives. Original articles, clinical trials, systematic reviews, and meta‐analyses from 1980 to 2021 were searched using the following terms: Graves’ disease, Graves’ orbitopathy, thyroid eye disease, glucocorticoids, orbital radiotherapy, rituximab, cyclosporine, azathioprine, teprotumumab, TSH‐receptor antibody, smoking, hyperthyroidism, hypothyroidism, thyroidectomy, radioactive iodine, and antithyroid drugs. This article is protected by copyright. All rights reserved
Chapter
Autoimmune thyroid diseases (AITD) include Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). HT is the most common autoimmune condition in the general population and the most frequent pediatric thyroid disease. GD is a relatively rare disease, but it is considered by far the most important cause of hyperthyroidism in the pediatric age. AITD are both characterized by lymphocytic infiltration of the thyroid parenchyma and by the production of different antibodies against thyroid antigens. The development of AITD is complex and involves a combination of genetic susceptibility as well as environmental triggering factors. Clinical and biochemical features are related to hyperthyroidism in GD, while HT may exhibit a huge variability of thyroid function patterns. The aim of this chapter is to report the most updated views on epidemiology, pathophysiology, diagnosis, long-term prognosis, treatment, and management of AITD in childhood and adolescence.
Article
Objective: The aim of this prospective study was to describe demographic and clinical characteristics of neonates born to mothers with active or past Graves disease and to assess compliance since implementation of a new protocol in our center. Methods: We prospectively followed up neonates born to mothers with active or past Graves disease in a tertiary hospital in Spain between August 2019 and September 2021 according to our protocol. We reviewed maternal and neonatal history of these neonates, and we followed up newborns at risk of neonatal hyperthyroidism. Results: Among 5808 births, 33 neonates were born to mothers with active or past Graves disease (0.57%). Six mothers (18.2%) had positive levels of thyroid-stimulating hormone receptor antibodies during pregnancy and five mothers (15.1%) between weeks 20 and 24 of pregnancy. Two of them had received definitive therapy for Graves disease before pregnancy. Two neonates (7.1%) were at high risk of neonatal hyperthyroidism and were followed-up until two months, without hyperthyroidism signs or abnormal thyroid hormone levels. Compliance of protocol during pregnancy was 84.9% and 75.8% at birth. Conclusions: Prevalence of Graves disease among pregnant women was 0.57%, with no cases of neonatal hyperthyroidism. Compliance of protocol was adequate during pregnancy (84.9%) and acceptable at birth (75.8%).
Article
Thyroid disease is associated with adverse maternal and fetal outcomes. Appropriate reference ranges should be used for the interpretation of test results, although universal screening for thyroid dysfunction is not warranted. Overt thyroid dysfunction requires careful consideration of medication adjustments and close monitoring. Mild thyroid hypofunction has been linked to adverse pregnancy outcomes including preterm delivery, and poor neurocognition in the offspring. This review summarizes the most recent evidence on the counseling and management of women with thyroid disease before and during pregnancy and highlights the areas of controversy in need of further research.
Article
Full-text available
Graves' hyperthyroidism and multinodular toxic goiter lead to high serum T(3) compared with serum T(4). The source of this high T(3) has not been clarified. Our objective was to assess the role of iodothyronine deiodinase type 1 (D1) and type 2 (D2) for T(3) production and to estimate the sources of T(3) in hyperthyroidism. The study was a prospective, randomized, open-labeled study in a secondary care setting. Consecutive patients with hyperthyroidism caused by Graves' disease or by multinodular toxic goiter were randomized to be treated with high-dose propylthiouracil (PTU) to block D1, PTU plus KI, or PTU plus sodium ipodate to additionally block D2. T(3) and T(4) were measured in serum, and we estimated the sources of T(3). PTU reduced the T(3)/T(4) in serum to 47.7 +/- 2.5% (mean +/- sem) of the initial value on d 4 of therapy in patients with Graves' disease. The addition of KI to PTU led to a greater fall in T(3) and T(4), but the balance was unaltered. After PTU plus ipodate, T(3)/T(4) on d 4 was lower, 34.1 +/- 1.2% of the initial value. Similar variations were observed in patients with multinodular toxic goiter. Thus, the major source of the excess T(3) was D1-catalyzed T(4) deiodination, with a minor role for D2. It was estimated that the majority of this D1-catalyzed T(3) production takes place in the hyperactive thyroid gland. Although thyroidal T(3) contributes only around 20% of total T(3) production in normal individuals, this is much higher in patients with a hyperactive thyroid, ranging up to two thirds. The major part is produced from T(4) deiodinated in the thyroid.
Article
Quantification of thyrotropin-receptor antibodies is important in the diagnosis and management of patients with Graves disease (1). Antibodies with stimulating activity (TSI) have traditionally been detected in bioassays that measure their effect on cloned rat thyroid cells (FRTL-5) or on Chinese hamster ovary (CHO) cells transfected with recombinant human thyrotropin-stimulating hormone (TSH) receptor (2)(3). These assays can detect antibodies in up to 95% of untreated hyperthyroid Graves patients, but, with few exceptions (4), they require cell culture facilities and are labor intensive and time consuming. As an alternative to bioassays, several manufacturers have developed competitive immunoassays that measure the inhibition of the binding of labeled TSH by antibodies in patients’ sera. These methods use porcine TSH receptors and claim clinical sensitivities of ∼90%. They cannot, however, distinguish whether the autoantibodies have blocking or stimulating capabilities, which can be important in a subset of patients. The more recent LUMItest® TRAK (TRAK) human assay (BRAHMS AG) uses human recombinant TSH receptors and luminescence-labeled bovine TSH. The manufacturer’s literature cites a clinical trial that achieved a diagnostic sensitivity of almost 99% with the research version of the DYNOtest® TRAK human assay (5). We have been performing the TSI bioassay with FRTL-5 cells routinely for more than 15 years. The TSI test volumes have increased steadily over that time, requiring an ever-increasing number of assays each week. In 1998, we added the Kronus® TRAb radioreceptor assay (TRAb) to our test menu to reduce the number of requests for TSI. During the preimplementation evaluation of the Kronus reagents, we found equivalent results in 80 of 89 random patient samples. Of the remaining nine samples, five were positive by TSI and not by TRAb, and four were positive by TRAb and not by TSI. The availability of the BRAHMS reagents as well as …
Article
Pretibial myxedema or localized myxedema or thyroid dermopathy is an autoimmune manifestation of Graves’ disease. It also occasionally occurs in Hashimoto’s thyroiditis. Lesions of thyroid dermopathy are usually asymptomatic and have only cosmetic importance. Advanced forms of dermopathy are associated with elephantiasis or thyroid acropachy. Almost all cases of thyroid dermopathy are associated with relatively severe ophthalmopathy. Usually ophthalmopathy appears first and dermopathy much later. All patients with localized myxedema have high serum concentrations of thyroid-stimulating hormone receptor antibodies, indicating the severity of the autoimmune condition. Occurrence of thyroid dermopathy in areas other than pretibial skin indicates a systemic process. Similar to Graves’ ophthalmopathy, thyroid-stimulating hormone receptors in the connective tissue may be the antigen responsible for the immune process. Both humoral and cellular immune mechanisms are involved in the stimulation of fibroblasts and the production of large amounts of glycosaminoglycans. Localization in the pretibial area relates to mechanical factors and dependent position.
Article
Ophthalmopathy caused by Graves' disease may first appear or worsen during or after treatment for hyperthyroidism. It is not known, however, whether choosing to treat hyperthyroidism with antithyroid drugs, iodine-131, or surgery affects the development or aggravation of Graves' ophthalmopathy. We studied 168 patients with hyperthyroidism caused by Graves' disease, stratified into two age groups--20 to 34 years (54 patients, group 1) and 35 to 55 years (114 patients, group 2). The patients in group 1 were randomly assigned to treatment with methimazole for 18 months or subtotal thyroidectomy, and those in group 2 to either of these two treatments or to iodine-131 therapy. All the patients received thyroxine to avert hypothyroidism, except those treated with iodine-131, who received thyroxine only if hypothyroidism developed. The duration of follow-up was at least 24 months. Twenty-two patients (13 percent) had infiltrative Graves' ophthalmopathy at randomization. During follow-up, ophthalmopathy developed for the first time in 22 patients (13 percent) and worsened in 8 patients (5 percent). The frequency of the development or worsening of ophthalmopathy was similar among the patients in group 1 (medical therapy, 4 of 27 patients [15 percent]; and surgery, 3 of 27 patients [11 percent]). In group 2, ophthalmopathy developed or worsened in 4 of the 38 patients (10 percent) treated medically, 6 of the 37 patients (16 percent) treated surgically, and 13 of the 39 patients (33 percent) given iodine-131 (P = 0.02 for the comparison between the iodine-131 subgroup and the others combined). The risk of the development or worsening of ophthalmopathy increased as pretreatment serum triiodothyronine concentrations increased. As compared with other forms of antithyroid therapy, iodine-131 is more likely to be followed by the development or exacerbation of Graves' ophthalmopathy.
Article
Only a minority of patients with hyperthyroidism caused by Graves' disease will experience cure of disease with a permanent euthyroid state without medication. Antithyroid drugs are useful in attaining euthyroidism, and most patients will gradually enter remission of the autoimmune abnormality after becoming euthyroid. A stable euthyroid state may be sustained by prolonged low-dose medication. The risk of relapse of hyperthyroidism after withdrawal of medication seems to be independent of duration of therapy, once remission has been induced. A number of risk factors influence the outcome of therapy and they should be evaluated when planning duration of therapy with antithyroid drugs.
Article
Among the 504 patients with Graves' disease in whom the author initiated antithyroid drug therapy between 1956 and 1968 are 14 to whom the administration of antithyroid drug has been continued for 8 to 21 years because of recurrence shortly after the discontinuation of drugs. During these periods, no side effects were observed and three patients went into complete remission after 8, 9 and 20 years of antithyroid drug administration, respectively. It is suggested therefore that the long term administration of antithryoid drugs can be a useful treatment for intractable cases.
Article
The major drawback to treatment of hyperthyroidism with antithyroid compounds is the reported low rate of remission. Eighty patients have been given long-term (at least one year; average, 4.4 years; range, one to 14 years) continuous treatment with a remission rate of 76% and an average follow-up of 7.8 years (one to 21 years). The prognostic test of suppressed uptake by the thyroid of less than 20% was about 75% accurate in predicting continuing remission when treatment was stopped. Of those in remission, 14 (23%) were treated for one year, 35 (57%) for one to five years, and 12 (20%) for more than five years. Mild reactions occurred in five (6%), hypothyroidism in two (3%). An antithyroid drug is safe and effective therapy for hyperthyroidism.
Article
The effects of methimazole or betamethasone therapy on the TSH receptor antibody response to radioiodine therapy were compared in a prospective randomized study of 60 patients with hyperthyroidism due to Graves' disease. The patients were followed for 1 yr after treatment with 131I. Twenty-three patients received 131I alone, 17 were treated with methimazole for 2 months before and 3 months after 131I therapy, and 20 patients were treated with betamethasone for 3 weeks before and 4 weeks after 131I therapy. 131I induced a transient rise in the mean serum level of TSH receptor autoantibodies, measured as TSH binding inhibitory immunoglobulin (TBII), but in patients receiving methimazole treatment, no such rise occurred. In the betamethasone-treated patients, TBII increased similarly to that in patients treated with 131I alone. In addition, in patients given betamethasone, there was an early decrease in total serum immunoglobulin G, which persisted throughout the follow-up period. In the other 2 groups, no changes in total immunoglobulin G were found. The results demonstrate that in hyperthyroid Graves' disease, TBII production is influenced by therapy. Methimazole abolished the 131I-induced increase in TBII, whereas betamethasone did not have such an inhibitory effect.
Article
Twenty-six patients with Graves' hyperthyroidism treated only with propranolol for 1-21 months have been followed up to 5 years. The patients were evaluated before treatment, at 15, 30, and 90 days during treatment, and then at 90-day intervals during propranolol treatment by clinical examination and measurement of serum free T3, free T4, rT3, TSH, and sex hormone-binding globulin concentrations and serum anti-thyroglobulin, antithyroid microsomal, antithyroid peroxidase, and thyroid-stimulating autoantibodies. Eighteen patients who had no biochemical improvement during propranolol therapy or relapsed after initial improvement were treated conventionally. In contrast, eight patients had a biochemical remission, which has lasted 30-48 months after propranolol withdrawal. The biochemical values before and during treatment did not differ among the two groups of patients, except for the initial serum free T3 levels which were significantly higher in the patients who had no remission. Serum TSH levels returned to normal only in patients who had a long-lasting remission. While thyroid autoantibodies decreased or disappeared during follow-up, the evolution of thyroid-stimulating autoantibody values was grossly related to the clinical outcome. Long-lasting remissions may occur in patients with hyperthyroidism due to Graves' disease not given ablative or antithyroid drug therapy. Since propranolol is devoid of antithyroid and immunosuppressive actions, these remissions are probably spontaneous. Although they tended to occur in patients with less severe disease, no biological parameter was found that predicted the outcome.