The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 616-619
Copyright © 1997 by The Endocrine Society
Incomplete Thyrotroph Suppression Determined by Third Generation Thyrotropin Assay in Subacute Thyroiditis Compared to Silent Thyroiditis or Hyperthyroid Graves’ Disease
Mitsuru Ito,
Junta Takamatsu,
Shigeru Yoshida,
Yasuhiro Murakami,
Sadaki Sakane,
Kanji Kuma and
Nakaaki Ohsawa
First Department of Medicine, Osaka Medical College, Takatsuki,
(M.I., J.T., S.Y., Y.M., S.S., N.O.); and the Kuma Hospital, Kobe,
(K.K.), Japan
Address correspondence and requests for reprints to: Dr. Junta Takamatsu, Associate Professor of First Department of Medicine, Osaka Medical College, 2-7, Daigakumachi, Takatsuki City, Osaka 569, Japan.
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Abstract
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Serum TSH concentrations were determined by both second and third
generation assays in three types of thyrotoxicosis associated with
subacute thyroiditis, silent thyroiditis, and hyperthyroid Graves’
disease at the time of each patient’s initial visit to the clinic.
Serum TSH concentrations as measured by the second generation assay
with an analytical sensitivity of 0.04 mU/L were below the detection
limit in every patient. In contrast, serum TSH concentrations as
measured by the third generation assay with an analytical sensitivity
of 0.009 mU/L were below the detection limit in 18 of 21 (86%)
patients with Graves’ disease, 18 of 20 (90%) with silent
thyroiditis, but only 4 of 18 (22%) with subacute thyroiditis. Changes
in serum TSH concentrations were studied in healthy volunteers given
daily 75 µg of T3; their serum TSH concentrations on the
second generation assay fell below the detection limit within 3 days in
every subject. However, the TSH concentration measured by the third
generation assay remained above the detection limit in 6 of 8 normal
subjects even on the 14th day of therapy.
The reason for incomplete TSH suppression in most subacute thyroiditis
patients may be that these patients had notable neck pain, and their
initial visit to the clinic may have occurred earlier after the onset
of disease than with patients who have had silent thyroiditis or
Graves’ disease. Thus, the serum TSH concentration had not decreased
sufficiently below the detection limit at the time blood was drawn. The
data suggest also that the highly sensitive TSH assay, if the level is
above the detection limit, can be used to suppose that the short
duration of the initiation of thyrotoxicosis indicates a case of
subacute thyroiditis. .
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Introduction
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THE NEW chemiluminescence assay of serum
TSH concentrations, designated the ultrasensitive assay or third
generation assay, helps distinguish partial from more complete
thyrotropic suppression (1, 2, 3, 4). For example, most patients with
Graves’ disease have been reported to have serum TSH concentrations
below the detection limit as measured by third generation assays (1, 4), while in patients receiving thyroxine as replacement therapy or
suppressive therapy, serum TSH concentrations are occasionally below
the detection limit with the second generation assay but above the
detection limit with the third generation assay (1, 2, 4).
In the present study, we determined serum TSH concentrations using the
third generation assay in three types of thyrotoxicosis including
subacute thyroiditis, silent thyroiditis, and hyperthyroid Graves’
disease. In addition, a protocol of triiodothyronine (T3)
administration to healthy volunteers was performed to help clarify the
pathogenesis of incomplete TSH suppression in subacute thyroiditis.
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Materials and Methods
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Patients
Three groups of patients with untreated thyrotoxicosis were
studied. They included 21 with hyperthyroid Graves’ disease (2 men and
19 women), 20 with silent thyroiditis (1 man and 19 women), and 18 with
subacute thyroiditis (1 man and 17 women). The diagnosis of Graves’
disease was established on the basis of thyrotoxic symptoms with
diffuse goiter, elevated serum thyroid hormone levels, increased
radioactive iodine uptake, and positive serum TSH receptor antibody
activity. The diagnosis of silent thyroiditis was made by elevated
serum thyroid hormone levels and very low radioactive iodine uptake,
together with painless goiter, on the basis of chronic thyroiditis. The
diagnosis of subacute thyroiditis was established by elevated serum
thyroid hormone levels, positive C-reactive protein, and very low
radioactive iodine uptake, together with the typical symptoms of
thyroid gland tenderness. Table 1
summarizes the thyroid
function of patients from three groups of thyrotoxicosis.
Administration of T3 to healthy volunteers
Eight normal subjects (6 men and 2 women) with no clinical,
historical, or biochemical evidence of thyroid disease were studied
after each provided written informed consent. Each subject received 25
µg of T3 orally three times per day for two weeks.
TSH assays
Serum was collected at the time of each patient’s initial visit
to our clinic. The third generation assay for serum TSH was performed
using a chemiluminescence immunometric assay (Amerlite TSH-30:
Ortho-Clinical Diagnostics K.K. (Tokyo, Japan) (4). The normal range
was 0.30 
3.90 mU/L, and the limit of analytical sensitivity
(5), defined as the value 2 SD above the zero standard
determined from a mean of 20 replicates, was 0.009 mU/L. The intrassay
precisions (CV) were 4.4% at 0.12 mU/L, 2.5% at 6.5 mU/L, and 4.2%
at 32.5 mU/L. The interassay precisions (CV) were 6.3% at 0.12 mU/L,
2.5% at 6.5 mU/L, and 3.3% at 32.5 mU/L. Every serum sample was
measured simultaneously for TSH using a second generation
chemiluminometric assay (Amerlite TSH-60: Ortho-Clinical Diagnostics
K.K.), in which the analytical sensitivity was 0.04 mU/L.
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Results
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Serum TSH concentrations determined by second and third
generation assays
As shown Fig. 1A, serum TSH concentrations
determined by the second generation assay were below the detection
limit in every patient from the three groups. As shown in Fig. 1B, the
serum TSH concentrations, as measured by the third generation assay,
differed from those measured by the second generation assay. By the
third generation assay, 18 of the 21 (86%) patients with Graves’
disease and 18 of the 20 (90%) patients with silent thyroiditis had
serum TSH concentrations below the detection limit. In contrast, only 4
of the 18 (22%) patients with subacute thyroiditis had serum TSH
concentration below the detection limit, and the remaining patients
(78%) had a serum TSH above the detection limit.
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Figure 1. Serum TSH concentrations in three types of
thyrotoxicosis as determined by second (A) and third (B) generation
assays. Shaded areas represent the normal range. The
broken lines correspond to the detection limit of the assay.
Open circles correspond to patients with a serum TSH below
the detection limit, while the closed dots correspond to
those with a serum TSH above the detection limit.
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Serum TSH concentrations in relation to serum free
T4 concentrations
Figure 2 demonstrates the relationship
between serum free T4 and TSH concentrations in three
groups of thyrotoxic patients. Two of three patients with Graves’
disease with detectable serum TSH had a relatively mild increase in
serum free T4. In patients with silent thyroiditis, the
increase of the serum free T4 concentrations was not
remarkable compared with that of the other two groups; however, most of
these subjects had undetectable serum TSH concentrations.
In subacute thyroiditis, serum TSH concentrations were not suppressed
completely even in three patients whose serum free T4 was
remarkably high.
Serum TSH concentrations in relation to duration of subacute
thyroiditis
When patients with subacute thyroiditis were classified into four
subgroups according to the time after the initial appearance of thyroid
pain, as shown in Fig. 3, the serum TSH concentrations
tended to decrease with time after the onset of pain. The mean serum
TSH concentration within one week after the onset of pain was
significantly higher (P < 0.05) than when measured at
2, 3, or 4 weeks after the onset of pain.
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Figure 3. Serum TSH concentrations in patients with subacute
thyroiditis classified according to the duration from the onset of
thyroidal pain to the time of blood sampling. The broken
line indicates the detection limit of sensitivity. The
bars indicate the mean value of each group. *indicates
significant difference (P < 0.05) from the data at
0–1 weeks of disease duration.
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T3 administration in healthy volunteers
As shown in Fig. 4, serum TSH concentrations, as
measured by the second generation assay, were decreased below the
detection limit in every subject within three days. Serum TSH
concentrations, as measured by the third generation assay fell rapidly
within a day. However, the decrease in serum TSH became gradual after
the second day and could be detected in 6 of 8 subjects even on day
14.
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Figure 4. Changes in serum TSH concentrations as measured by
second and third generation assays (A and B, respectively) during the
course of daily T3 administration (75 µg) for two weeks
to healthy volunteers (• or  ). Open symbols represent
the TSH value below the detection limit. The broken lines
indicate the detection limit of each TSH assay.
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Discussion
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The major finding of the present study was that many subacute
thyroiditis patients (78%) had serum TSH concentrations above the
detection limit on the third generation assay, while such incomplete
TSH suppression was not observed in most patients with silent
thyroiditis and Graves’ disease. One explanation might be that the
rate of increase of serum thyroid hormone concentration was not as
great in the subacute thyroiditis as in the other two groups. However,
the serum free T4 concentration in patients with subacute
thyroiditis was not lower and was, in fact, higher than in those with
silent thyroiditis (Fig. 2
), indicating that the incomplete TSH
suppression in subacute thyroiditis may have other causes.
The duration of subacute thyroiditis revealed that serum TSH
concentrations declined with disease duration (Fig. 3). When
T3 was administered to healthy volunteers, serum TSH
declined gradually in a nonlinear manner, and the serum TSH remained
above the detection limit until the 14th day in 6 of 8 subjects (Fig. 4). Indeed, it was previously reported that suppression of TSH by
thyroid hormone therapy is a biphasic and nonlinear process (6). These
facts suggest that serum TSH is not suppressed completely in short-term
thyrotoxicosis. Thus, subacute thyroiditis patients may have incomplete
TSH suppression as they present earlier to the clinic because of neck
pain than do those patients with silent thyroiditis or Graves’
disease. In contrast, patients with silent thyroiditis or Graves’
disease seek medical assistance for thyrotoxic symptoms, such as
palpitation and weight loss, which developed later in the course of the
disease, and at the time of initial examination may have their serum
TSH concentration suppressed below the limit of detection.
It is also possible that the differences in serum TSH levels between
two types of transient thyrotoxicosis of subacute thyroiditis and
silent thyroiditis may be explained by a difference in how
thyrotoxicosis develops. Although thyrotoxicosis of these two disorders
is thought to be a result of destruction of thyroid follicles followed
by a release of thyroid hormone into the circulation, the development
of silent thyroiditis is probably more gradual than that of subacute
thyroiditis, because the manner of thyroid destruction in the two
disorders may differ. Although not completely understood, silent
thyroiditis is an autoimmune process (7, 8, 9), and subacute thyroiditis
may relate to viral infection (10). The data herein may lend support to
different methods of developing thyrotoxicosis between these two forms
of thyroiditis. Determination by sensitive TSH assay in the other,
relatively unique types of thyrotoxicosis, including transient
thyrotoxicosis with thyroid gland pain in the setting of chronic
thyroiditis (11) or Graves’ disease associated with thyroidal pain
(12), may merit further investigation, because it has been reported
that in painful thyrotoxicosis with chronic thyroiditis, the duration
of pain at the initial visit does not differ from that of the usual
patients with subacute thyroiditis (11).
Finally, it may be difficult to diagnose subacute thyroiditis by the
TSH measurement alone because approximately 20% of patients with this
disorder had a serum TSH level below the detection limit. Its
characteristic symptoms and physical signs, very low 123I
thyroidal uptake and positive inflammatory reaction, together will help
make the correct diagnosis. The third generation TSH assay will help
provide some additional information to care for patients with subacute
thyroiditis. The highly sensitive serum TSH determination may be used
to determine the onset of thyrotoxicosis; a subnormal but detectable
TSH indicates that the period of thyrotoxicosis is relatively short, as
in the case of subacute thyroiditis, while an extremely low TSH level
indicates a longer duration of thyrotoxicosis, as in the case of silent
thyroiditis or hyperthyroid Graves’ disease.
Received April 11, 1996.
Revised September 12, 1996.
Accepted October 14, 1996.
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Top
Abstract
Introduction
), and Graves’ disease (
). Open
symbols (
, and 
) correspond to patients with a serum TSH
below the detection limit. The shaded area represents the
normal range of serum free T4 or TSH concentration. The
broken line corresponds to the detection limit of
sensitivity of the third generation assay.