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.


    Introduction
 Top
 Introduction
 Case Report
 Discussion
 References
 
Subacute (De Quervain’s) 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 Quervain’s 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.


    Case Report
 Top
 Introduction
 Case Report
 Discussion
 References
 
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 1Go). 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 1Go). 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 1Go). 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

 
Hormone assay

Plasma free T3 and free T4 (normal range, 2.2–5.5 pg/mL and 6.0–18.0 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 patient’s serum and the negative controls were tested at several dilutions. All sera were tested blindly three times, and no interassay variation was reported.


    Discussion
 Top
 Introduction
 Case Report
 Discussion
 References
 
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 7–8 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.


    References
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 Introduction
 Case Report
 Discussion
 References
 

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