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
, Leif Tallstedt
, Mirna Abraham-Nordling
and Ove Tørring
Department of Endocrinology and Internal Medicine, Aalborg Hospital, Aarhus University Hospital, DK-9000 Aalborg, Denmark,
Department of Molecular Institution of Surgery, Karolinska University Hospital, Stockholm, Sweden,
Department of Ophthalmology, Karolinska
Institutet, St Erik’s Eye Hospital, Stockholm, Sweden,
Radiumhemmet, Department of General Oncology, Karolinska University Hospital, Stockholm,
Department of Endocrinology and Internal Medicine and Institution of Clinical Research and Education, So¨dersjukhuset, Karolinska Institutet,
(Correspondence should be addressed to P Laurberg; Email: email@example.com)
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-
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).
) 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Anti-thyroid drugs were withdrawn after 18 months of therapy.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
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 ﬂuctuate 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
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
medical therapy) or subtotal thyroidectomy followed by
(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 (
) was 6.3 (2.0) nmol/l, T
239 (72) nmol/l, and free
59 (26) pmol/l in young patients (nZ30); mean (S.D.)
was 5.4 (1.7) nmol/l, T
224 (55) nmol/l, and free T
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,
in doses of 0.1–0.3 mg per day to keep a normal serum
and a slightly suppressed serum TSH. L-T
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
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.
started around day 4 after surgery to avoid hypothyr-
oidism. At the time of inclusion, mean (
S.D.) serum T
was 5.6 (1.8) nmol/l, T
was 221 (46) nmol/l, and
was 60 (24) pmol/l in young patients (nZ30),
while in old patients T
was 5.4 (1.9) nmol/l, T
(55) nmol/l, and free T
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
Forty-one patients were randomized to
therapy. This was given as a single oral dose calculated
to deliver 120 Gray units to the thyroid.
initiated as soon as serum TSH was elevated and/or when
serum free T
were low. At the time of inclusion,
S.D.) serum T
was 5.3 (1.7) nmol/l, T
(57) nmol/l, and free T
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
therapy (12). All patients treated with radioiodine
substitution therapy for
All TSH receptor antibody (TRAb) measurements were
performed by a radioreceptor assay kit provided by RSR
Ltd, Cardiff, UK. In this method,
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
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
P Laurberg and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158
(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.
, and free T
were measured as described
previously (11). The reference ranges were: T
1.1–2.5 nmol/l; T
Patients were included after informed consent, and
the protocol was approved according to Swedish ethics
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,
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
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
-test (comparison of
percentages). The level of signiﬁcance was set at 5%.
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
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
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).
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 ﬁrst 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
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 difﬁcult-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
(11). In Graves’ disease, disproportionately high serum
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
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
Graves’ disease during pregnancy. However, even if the
woman is made hypothyroid by radioiodine and
subsequently euthyroid by
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
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.
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
PL: Research Support by BRAHMS Diagnostica, Berlin,
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Received 21 September 2007
Accepted 8 October 2007
Therapy and TSH-receptor antibodies
75EUROPEAN JOURNAL OF ENDOCRINOLOGY (2008) 158