DISCUSSION
Ophthalmopathy, which is one of the extrathyroidal components of Graves' disease, sometimes emerges in euthyroid patients with no history of thyrotoxicosis. (euthyroid Graves' disease). The pathogenesis of the ophthalmopathy in Graves' disease, euthyroid or otherwise, is still unknown. Since lymphocytic infiltration is observed in the retroorbital tissue, it has been suggested that an autoimmune reaction against the retroorbital tissue is the cause of Graves' ophthalmopathy [3-5] .
The hyperthyroidism in Graves' disease is caused by autoantibodies against TSH receptor, which stimulates the production of thyroid hormone by thyroid epithelial cells. TBII, measured by a kit of radio-receptor assay from Cardiff, UK (TRAb 'Cosmic', Cosmic Co., Tokyo, Japan), can be detected in about 95% of patients with Graves' disease. With a more sensitive bioassay, TSAb is found in almost all patients with Graves' disease [1] . Consistent with this, distribution analysis has revealed exophthalmos in almost all patients with Graves' disease [6] . Patients with euthyroid Graves' disease often show some abnormalities upon thyroid examination [4] . The reported incidence of various thyroid abnormalities is as follows: presence of thyroid enlargement, 24-40%; low TSH, 14-23%; no or low response of TSH to TRH, 40-63%; high thyroid uptake of 123I, about 20%; negative T3-suppression test, 30-73%; positive TgAb, 11-67%; positive McAb, 18-60%; positive TBII, 31-36%; and positive TSAb, 43-87% [1, 7-12] . Among these abnormalities, that of TSAb can be detected most often in euthyroid Graves' disease. We recently detected TSAb in the serum of 93% of our patients with euthyroid Graves' disease by using an ultrasensitive assay for TSAb we have developed, which detects 0.1 ｵU/ml of bTSH and is one thousand times more sensitive on the base of bTSH than TBII assay ( [13, 14] ; unpublished data). This incidence was almost the same as that in patients with hyperthyroid Graves' disease. Furthermore, this TSAb assay was useful in the prediction of the onset of Graves' disease after delivery [14] . However it was reported that in a few of hyperthyroid Graves' disease patients, both radioreceptor assay and bioassay could not detect any antibodies [15] . Subsequent to radioiodine therapy, TSH receptor antibodies appeared in almost all of their patients. Considering all, a local production of TSAb within thyroid gland and may be in retroorbital tissue is important in the patients with Graves' disease associated with ophthalmopathy. Moreover follow-up study is essential in these patients.
Our patients showed no goiter, with euthyroidism, normal TSH concentration, normal 123I-uptake, normal T3 suppression, and negative McAb, TgAb, and TBII. However, their ocular symptoms and the enlargement of the extraocular muscles demonstrated by MRI were typical findings in Graves' ophthalmopathy. Furthermore, TSAb activities were positive as measured with our ultrasensitive assay. Thus, we diagnosed them as having euthyroid Graves' disease. While there are many reports regarding this disease, this is the first report to our knowledge of patients with euthyroid Graves' disease showing no thyroid abnormalities other than positive TSAb.
It was recently reported that TSH-receptors are present on retroorbital tissue [16] . Therefore, TSH receptor antibody stimulating thyroid cells (TSAb) might also stimulate or interact with retroorbital tissue, causing ophthalmopathy. Indeed, the change in TSAb activity almost paralleled the extent of ophthalmopathy in our patients. Furthermore, we found that the TSAb activity was also related to the degree of ophthalmopathy in patients with hypothyroid Graves' disease, who present Graves' ophthalmopathy and TSAb, but are hypothyroid due to the practical destruction of the thyroid [2] . Given these considerrations, TSAb might be important in the development of Graves' ophthalmopathy.
The mechanism by which euthyroid condition was maintained in our patients even though they had positive TSAb is unknown, but it might be either that the TSAb activity was not high enough to cause hyperthyroidism in euthyroid Graves' disease or the presence of a suppressive mechanism against TSAb stimulation in euthyroid Graves' disease. Alternatively, an antigenic epitope on the TSH-receptor recognized by TSAb in euthyroid Graves' disease may differ from that in usual Graves' disease, or there may be other differences between the two forms of the disease.
In any event, the measurement of TSAb in patients who have ophthalmopathy without other thyroid abnormalities is essential to accurate diagnosis.
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