12 of 17, a significant frequency (71%), of untreated Graves' disease patients with no clinical ophthalmopathy showed extraocular muscle (EOM) enlargement by Magnetic Resonance Imaging (MRI). Enlargement was bilateral in 41% and unilateral in 29% in these patients. Apparent enlargements of EOM were also detected, by MRI, in all of 11 Graves' disease patients with clinical ophthalmopathy, bilateral in 73% and unilateral in 27% of patients in this group. Both group showed the inferior rectus muscle as the most frequently involved (56% and 77% respectively). In 16 patients without autoimmune thyroid disorders or ophthalmopathy who served as normal controls, only 2 of these patients (12%) demonstrated mild EOM enlargement. The severity and patterns of EOM enlargement revealed no correlation with abnormalities in serum thyroid function tests or serum thyroidal autoantibodies. In conclusion, a high frequency of Graves' disease patients without clinical eye signs or symptoms harbor EOM abnormalities, as demonstrated by MRI. This suggests that present clinical examination methods are insufficient to diagnose varying degrees of ophthalmopathy in patients with autoimmune thyroid disorders who do not initially present with clinical ophthalmopathy.

To examine whether suppressive doses of thyroxine have any adverse effects on bone, we evaluated various bone metabolic markers (lectin-precipitated alkaline phosphatase, osteocalcin, carboxyl-terminal region of type I collagen propeptide, tartrate-resistant alkaline phosphatase, and urinary excretion of hydroxyproline and pyridinium crosslinks), incidence of vertebral deformity, total body and regional (lumbar spine and radius) bone mineral densities (BMDs), and rates of bone loss in 24 late postmenopausal (more than 5 years after menopause) women who were treated with levothyroxine (L-T4) after total thyroidectomy for differentiated carcinoma. Depending on the clinical records, including serum TSH levels measured by immunoradiometric assay, these patients were divided into two groups. One group of patients was given suppressive doses of L-T4 (TSH < 0.1 mU/L, n = 12) and the other group was given nonsuppressive doses of L-T4 (TSH > 0.1 mU/L, n = 12). There was no difference in bone metabolic markers and incidence of vertebral deformity between the groups. In patients with TSH suppression, Z-scores of BMDs calculated from age-matched healthy women (n = 179, aged 55 to 80) were nearly in the zero range of values (0.077 at total body, 0.228 at lumbar spine, and -0.117 at trabecular region of lumbar spine). The rate of bone loss in TSH-suppressed patients (-0.849 +/- 0.605%/year) was not significantly different from that of nonsuppressed patients (-0.669 +/- 0.659). These prospective and cross-sectional data suggest that long-term levothyroxine therapy using suppressive doses has no significant adverse effects on bone.

PTC gene, which is derived from the rearranged form of the ret proto-oncogene, was originally discovered in human thyroid papillary carcinomas. This gene has been thought to act as a tumorigenetic factor in thyroid carcinoma, although the action of PTC oncogene products is still unknown. To study the frequency of the PTC gene present in human thyroid carcinomas, we investigated four cell lines derived from thyroid carcinoma and 22 thyroid tumor tissue specimens. The reverse transcriptase-polymerase chain reaction (RT-PCR) method was performed to detect putative PTC mRNA. The presence of the PTC gene in genomic DNA was analyzed by Southern blot hybridization. PTC mRNA was detected by the RT-PCR method in only one papillary carcinoma cell line (TPC-1 cell). Southern gel analysis confirmed the rearrangement of the ret proto-oncogene in this cell line. In the other three cell lines and 22 tumor tissue specimens, however, neither the PTC gene or mRNA was detected. These results demonstrate that the prevalence of the PTC gene in thyroid tumor is low and may not be essential for human thyroid tumorigenesis. That our present results conflict with previous reports may be due to general differences in genetic background among races.

12 of 17, a significant frequency (71%), of untreated Graves' disease patients with no clinical ophthalmopathy showed extraocular muscle (EOM) enlargement by Magnetic Resonance Imaging (MRI). Enlargement was bilateral in 41% and unilateral in 29% in these patients. Apparent enlargements of EOM were also detected, by MRI, in all of 11 Graves' disease patients with clinical ophthalmopathy, bilateral in 73% and unilateral in 27% of patients in this group. Both group showed the inferior rectus muscle as the most frequently involved (56% and 77% respectively). In 16 patients without autoimmune thyroid disorders or ophthalmopathy who served as normal controls, only 2 of these patients (12%) demonstrated mild EOM enlargement. The severity and patterns of EOM enlargement revealed no correlation with abnormalities in serum thyroid function tests or serum thyroidal autoantibodies. In conclusion, a high frequency of Graves' disease patients without clinical eye signs or symptoms harbor EOM abnormalities, as demonstrated by MRI. This suggests that present clinical examination methods are insufficient to diagnose varying degrees of ophthalmopathy in patients with autoimmune thyroid disorders who do not initially present with clinical ophthalmopathy.

The effect of retinoic acid (RA) on thyroid peroxidase (TPO) and thyroglobulin (Tg) gene expression was investigated in cultured human thyrocytes. Thyrocytes dispersed from Graves' thyroid tissues were incubated with TSH 5mU/ml and RA 0, 0.01, 0.1, 1.0 microM for 72 h respectively. The samples were then subjected to Northern gel analysis. Northern gel analysis using the specific cDNA probes showed that RA suppressed the accumulation of TPO and Tg mRNA stimulated by TSH in a time- and dose-responsive manner. Furthermore, RA inhibited forskolin and 8-Bromo-cyclic-AMP-induced TPO and Tg gene expression, suggesting a distal action site for these cAMP mediated gene expressions. Immunoprecipitation analysis using the specific monoclonal antibodies showed that TSH increased newly synthesized 100, 75, 36-kDa [35S] TPO. The increased de novo TPO was markedly inhibited by RA. Tg secretion from monolayer cultures was measured by radioimmunoassay. RA also inhibited TSH-induced Tg secretion in a dose dependent manner. RA did not affect [3H] thymidine uptake into primary cultured human thyrocytes. In conclusion, RA inhibits the synthesis of TPO and Tg via the suppression of thyroid-specific gene expression although the exact site of RA action on these genes in human thyroids remains to be further elucidated. These results suggest that RA may play a regulatory role in Tg and TPO gene expression, subsequently resulting in the suppression of thyroid hormone synthesis.