Extraocular Muscle Antibodies Positivity as the Only Serum Marker of Euthyroid Graves Ophthalmopathy following Subacute Thyroiditis: Case Report
Giovanni Amato,
Mario Rotondi,
Ida Salzano,
Annamaria De Bellis,
Giuseppina De Felice,
Ciro Costagliola,
Antonio Bellastella and
Carlo Carella
Institute of Endocrinology (G.A., M.R., I.S., A.D.B., G.D.F., A.B.,
C.Ca.) and Eye Clinic (C.Co.), II University of Naples, 80128 Naples,
Italy
Address correspondence and requests for reprints to: Prof. Giovanni Amato, Via Orsi, 33, 80128 Naples, Italy.
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Introduction
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Subacute (De Quervains) thyroiditis (SAT) is a
self-limiting disease, usually followed by a recovery of normal
thyroid function even if long-term sequelae in such a condition has
been described (1). In fact, patients with a previous history of SAT,
in about 1% of cases (2), may develop hypothyroidism as a consequence
of previous thyroid damage. The occurrence of Graves disease after
SAT has also been described, although such evenience seems to be
extremely rare with less than 15 cases reported in the literature
(3, 4, 5, 6, 7, 8, 9, 10, 11). Moreover, the physiopathologic mechanisms of hyperthyroidism
that occur after complete recovery of SAT are still unclear. A commonly
accepted hypothesis is that Graves disease may develop in genetically
predisposed individuals after SAT (12, 13). Several authors have
suggested that thyroid-destructive events in the course of De
Quervains thyroiditis may trigger, under certain circumstances,
thyroid autoimmune disease of various kinds (8, 10, 14). In the
previously reported cases, Graves ophthalmopathy following SAT was
always associated with hyperthyroidism or to positivity for antithyroid
receptor antibodies (TR-Ab). Here, we describe the case of a Caucasian
male who developed euthyroid Graves ophthalmopathy 3 yr after a
proven SAT. To our knowledge, this is the first observation of
extraocular muscle autoantibodies (EOM-Ab) positivity in a patient with
euthyroid Graves previously affected by SAT and showing no other signs
of thyroid autoimmunity.
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Case Report
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A 53-yr-old Caucasian male, with no family history of thyroid
disease, came to our observation because of sudden pain and tenderness
in the anterior region of the neck. He referred palpitations
accompanied by diffuse sweating and heat intolerance. He also
complained of sore throat, fatigue, insomnia, and hand tremor. The
erythrocyte sedimentation rate was 62 mm/h. Laboratory data revealed
hyperthyroidism (Table 1
). Thyroidal
radioiodine uptake at 24 h was less than 2%, whereas the
scintigraphy was consistent with diffuse reduced uptake. An
echotomography of the thyroid showed a gland of 24 mL of volume with
diffuse hypoechogenicity. Two nodules of less than 2.0 cm of maximum
diameter were present in the left lobe. The fine-needle aspiration
biopsy of the nodular lesions demonstrated clusters of follicular cells
and a polymorphous inflammatory infiltrate of lymphocytes, histiocytes,
and multinucleated cells, all in close relationship to masses of
colloid material. A diagnosis of SAT was rendered, and the patient
received therapy of 30 mg/die prednisone for 1 month and 60 mg/die
propanolol for 2 weeks. The patient rapidly felt better, and 2 months
later thyroid parameters were found in the normal range (Table 1
). The
nodular aspect of the thyroid gland, visualized at ultrasound, induced
us to perform a mild suppressive L-T4
therapy; to avoid cardiac side effects (15), the serum TSH level
was not kept below 0.5 µU/mL. The patient assumed 100 µg/die
levothyroxine for 1 yr, after which he disattended further clinical or
biochemical evaluations. Thyroid parameters evaluated in the course of
L-T4 therapy always showed values within the
normal range. Three years later, the patient consulted a clinician for
the appearance of visual problems. The presence of bilateral lid
retraction with proptosis and restrictive ophtalmoplegia were
suggestive for Graves ophthalmopathy. Thus, after the exclusion of
systemic diseases, an accurate ophthalmologic examination including
echotomography and computed tomography scan of the orbits was
performed. Corrected visual acuity was 20/20 in both eyes; intraocular
pressure measured with a Goldmann tonometer (Haag-Streit,
Switzerland) mounted on a slit lamp was 18 mm Hg in both eyes.
The fundus oculi examination, observed after a dilation of the pupil
with Tropicamide (MSD-SPA, Italy) 1% eye drops did not give
significant signs of pathology. The tear function was assessed by the
Schirmer test. The Schirmer I was within the normal range; on the
contrary, the Schirmer II resulted pathological.
Exophthalmometry was 22 mm in the right eye and 24 mm in left eye (LE).
The echotomography of the orbit showed a bilateral enlargement of the
EOM with major involvement of the LE. In detail, the thickness of the
EOM (mm) were: 4.88 and 5.58 for the inferior rectus; 5.23 and 5.11 for
the superior rectus; 4.77 and 7.44 for the medial rectus; 4.30 and 6.51
for the lateral rectus; 4.42 and 5.58 for the superior obliquus; and
5.11 and 5.00 for the inferior obliquus in right eye and LE,
respectively. The optic nerve was not interested by the process.
Thyroid parameters and autoantibodies were assayed again, and all were
found normal (Table 1
). At echotomography, the thyroid gland volume was
16 mL with diffuse hypoechogenicity pattern. The two nodular lesions
were still present. A second fine-needle aspiration biopsy of the
nodular lesions was executed, and it showed follicular cells containing
abundant colloid together with lymphocytic infiltration, which lead to
the diagnosis of multinodular goiter. Finally, the EOM-Ab were assayed,
and their titer, expressed as end-point dilution titer, was 1:64 on
three subsequent evaluations, showing a strong positivity. A diagnosis
of Graves ophthalmopathy in a nonfibrous state was rendered, and the
patient has started adequate corticosteroid treatment.
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Table 1. Progression from subacute thyroiditis to Graves
ophthalmopathy. Behavior of serum thyroid hormones, antibodies, and
EOM-Ab from one episode to the other
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Hormone assay
Plasma free T3 and free
T4 (normal range, 2.25.5 pg/mL and 6.018.0
pg/mL, respectively) were assayed by RIA with Lysophase kits
(Technogenetics, Milan, Italy). Intra- and interassay variations and
sensitivities were 2.9%, 4.7%, and 0.6 pg/mL for free
T3 and 3.0%, 5.7%, and 0.8 pg/mL for free
T4, respectively. TSH levels (normal range, 0.25
and 3.5 µU/mL) were investigated by an ultrasensitive assay kit
(DiaSorin, Inc., Saluggia, Italy). Intra- and interassay
variability was 3.9% and 5.4%, respectively; sensitivity was 0.05
µU/mL. Antithyroglobulin antibodies (normal range, <100 U/mL) were
measured by using the immunoradiometric assay kit (Ares Serono, Milan,
Italy) with an intra-assay, interassay, and detection limit of 3.9%,
6.9%, and 5.0 U/mL, respectively. Antiperoxidase antibodies (normal
range, <10 U/mL) were tested by a RIA kit (DiaSorin, Inc.) with an intra-assay, interassay, and detection limit of
2.5%, 6.6%, and 0.7 U/mL, respectively. TR-Ab (normal range, <10
U/mL) were assayed by a RIA kit (DiaSorin, Inc.) with an
intra-assay, interassay, and detection limit of 7.0%, 10.4%, and 2.5
U/mL, respectively.
EOM-Ab assay
EOM-Ab were determined by a semiquantitative indirect
immunofluorescent test according to Mengistu et al. (16). In
particular, unfixed cryostatic sections (4 µm) of normal human eye
muscle obtained from normal subjects undergoing surgical correction of
strabismous and of human skeletal muscle tissues (quadriceps) obtained
from normal controls undergoing surgical correction of exposed fracture
were used as substrates. Patients and three controls serum samples
were incubated on both substrates, and subsequently fluorescein
isothiocyanate-coniugated rabbit antihuman immunoglobulins (IgG, IgA,
and IgM) (DAKO Corp., Glostrup, Denmark), diluted
1:40, were added. The positivity of the patients serum was revealed
on eye muscles substrate but not on skeletal muscle sections, whereas
the controls sera did not show any reactivity on both substrates.
Subsequently the patients serum and the negative controls were tested
at several dilutions. All sera were tested blindly three times, and no
interassay variation was reported.
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Discussion
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SAT is a self-limiting inflammatory disorder that may be rarely
accompanied by a thyrotoxic phase as a result of thyroid-destructive
phenomena (1, 2). Thyroid autoimmune diseases of various kinds,
following SAT, have been observed. On the other hand, euthyroid
Graves ophthalmopathy, a condition extensively described (17, 18),
has not yet been reported as a long-term sequela of SAT. Few reports
have described the occurrence of ophthalmopathy in Graves disease
after SAT (6, 10, 14). Moreover, ophthalmopathy was associated with
hyperthyroidism in all cases and to elevated TR-Ab when these
antibodies had been assayed (10, 14). The only observation of
ophthalmopathy occurrence in an euthyroid patient previously affected
by SAT is given by Likata et al. (14). However, the authors
have explained their finding by the observation of elevated titers of
serum TR-Ab accompanied by the visualization at ultrasound of an
atrophyc thyroid gland. The fact that our patient was affected by a
Graves ophthalmopathy, confirmed by the ultrasound analysis, 3 yr
after SAT is interesting and even surprising if we consider that the
patient did not show any other sign of thyroid autoimmunity. Recently,
the role of EOM as targets of the autoimmune reactions in
thyroid-associated ophthalmopathy (TAO) has been supported (19, 20, 21, 22);
therefore, the finding of elevated titers of EOM-Ab in our case is not
surprising. As previously reported, autoantibodies reactive against EOM
antigens are present in 75% of patients with TAO, and their presence
seems to be specific for TAO showing a good correlation with the
clinical parameters of eye disease (19, 20, 21, 22). Although it is a commonly
accepted hypothesis that ophthalmopathy results from an autoimmune
attack against autoantigens in EOM, the role of EOM autoantigens and
the clinical significance of the corresponding serum autoantibodies
have not been completely clarified. In the previously reported cases,
the EOM-Ab positivity was accompanied by elevated TSH receptor
antibodies, thus complicating the pathogenetic role played by the
different autoantibody. The strong positivity for EOM-Ab reported in
this case, together with the fact that no signs of thyroid autoimmunity
and particularly TSH receptor Ab could be detected, might contribute to
give a possible physiopathologic explanation of the clinical finding of
ophthalmopathy. However, the diagnosis of TAO was rendered only after
the exclusion of other causes of exophthalmus. In fact, the underhand
beginning with slow progression of the ophthalmopathy was against an
inflammatory genesis, a pseudo-tumor of the orbit, or an infection.
Moreover, our patient did not suffer for pain and ptosis, commonly
present in ocular myositis and in other inflammatory diseases. He did
not show scleritis, characteristic for the pseudo-tumor, nor palpebral
erythema, frequent in myositis and sarcoidosis. Finally proptosis was
quite symmetric and exophthalmos was not pulsating, excluding
retroorbital tumor and vascular lesion, respectively. The linkage
between the previous episode of SAT and the occurrence of
ophthalmopathy 3 yr later might be difficult to demonstrate, and no
help is given by the literature because such an association has never
been described before. However, several factors should be considered:
1) Graves disease with hyperthyroidism usually develops within a year
after recovery from SAT, although a lag period as long as 78 yr has
been reported in two cases (8); 2) patients with a previous history of
SAT may show mild thyroid dysfunction, ultrasonic abnormalities,
recurrent episodes, and defects of iodine organification for a long
time (23). These findings, together with the observation of the
transient appearance of TR-Ab (24) and the presence of multiple thyroid
autoantibodies over a period of 39 months (25) after SAT suggest that
unknown subtle alterations of the autoimmune system may persist for
years after the onset of SAT. Patients affected by euthyroid Graves
are in few cases without any stigmata of thyroid disease, but they may
become hyperthyroid months or years later, as reported earlier (18). We
cannot present our patient long-term outlook yet, but surely a strict
surveillance of thyroid function and autoimmunity will be interesting
in this case. In conclusion, by observation of this case, we suggest to
consider the possibility that the alterations of the immune system
after SAT may also involve EOM and that EOM-Ab may explain the
occurrence of ophthalmopathy in patients without any sign of thyroid
autoimmunity.
Received August 16, 1999.
Revised November 4, 1999.
Accepted November 22, 1999.
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