Risk of malignancy according to sub-classification of the atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) category in the Bethesda system for reporting thyroid cytopathology.

OBJECTIVE: According to the Bethesda System for Reporting Thyroid Cytopathology, atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is a heterogeneous category that includes cases with architectural and/or nuclear atypia insufficient to warrant classification as malignant neoplasms. The ambiguous and descriptive characteristics of the AUS/FLUS category mean that the impact of the present guidelines on repeat fine needle aspiration (FNA) is unclear. The present study reclassified AUS/FLUS cases into four sub-categories and then correlated them with histological or cytological follow-up data to clarify the risk of malignancy. METHODS: Ninety-four cases of AUS/FLUS with available follow-up data were reviewed and assigned to one of four sub-categories: (i) AUS-N (nuclear atypia); (ii) AUS-A (architectural atypia); (iii) AUS-O (predominant oncocytic changes); and (iv) AUS-N/A (both nuclear and architectural atypia). The four sub-categories were correlated with subsequent histological or cytological follow-up data, including core needle biopsy, resection, or repeat FNA. RESULTS: Malignancy was identified in 34 of 94 cases (36.2%). The upper limit estimate for malignancy was 43.6%, and the lower limit estimate was speculated as 9.8%. The malignancy rate was highest in cases within the AUS-N sub-category (65.8%, range 16.6%-78.1%). CONCLUSIONS: The present study suggests that cases in the AUS/FLUS category have a higher risk of malignancy than previously thought. Because of the heterogeneous nature of the AUS/FLUS category, further sub-classification might be more effective in achieving appropriate risk stratification and better clinical management.

Ethanol ablation of predominantly cystic thyroid nodules: evaluation of recurrence rate and factors related to recurrence.

AIM: To evaluate recurrence rate and associated risk factors for recurrence after ethanol ablation (EA) in patients with predominantly cystic thyroid nodules. MATERIALS AND METHODS: This observational study was approved by the Ethics Committee of the Institutional Review Board and informed consent for procedures was obtained. From April 2009 to April 2013, 107 consecutive patients with predominantly cystic nodules were treated using EA. Recurrence was defined as nodules showing a residual solid portion with internal vascularity, cosmetic problems remaining, or persistent symptoms, and patients who requested additional therapy to resolve their symptomatic or cosmetic problems. Delayed recurrence was defined as treated nodules that showed no recurrent features at 1 month, but showed newly developed recurrent features during the longer follow-up period. Multivariate analysis was used for variables to demonstrate the independent factors related to volume reduction. RESULTS: One month after EA, 18.7% of patients (20/107) showed recurrence. Among 87 patients with non-recurrence, 24.1% (21/87) showed delayed recurrence. The total recurrence rate was 38.3% (41/107). Patients with recurrence (n = 41) were treated using radiofrequency ablation (n = 28), second EA (n = 4), and refused further treatment (n = 9). These patients responded well to repeat EA and radiofrequency ablation. Multivariate analysis demonstrated that the initial nodule volume (>20 ml; p < 0.036) and vascularity (grade >1; p < 0.049) were independent predictors of volume reduction at last follow-up. CONCLUSIONS: The results revealed that although EA seemed to be effective during the initial period, delayed recurrence should be considered during longer-term follow-up. The independent predictors of recurrence were initial volume (>20 ml) and vascularity.

Basal STAT3 activities are negatively correlated with tumor size in papillary thyroid carcinomas.

BACKGROUNDS: Signal transducer and activators of transcription-3 (STAT3) plays a critical role in promoting survival and cell growth as well as facilitating angiogenesis and metastasis in several cancers. AIM: This investigation focused on evaluation of STAT3 activities in human papillary thyroid cancers (PTC). METHODS: STAT3 activities of nuclear extracts of tumor tissue were measured from 35 PTC patients using enzyme- linked immunosorbent assay-based kits. RESULTS: STAT3 activities of PTC tissues were significantly lower than those of surrounding normal thyroid tissues [0.36 (interquartile range 0.24-0.72) vs 0.50 (0.29-1.11) arbitrary units, p<0.01]. We further analyzed the association between STAT3 activity and clinicopathologic factors in PTC tissue. Tumors with size ≥2 cm displayed significantly lower STAT3 activities than those <2 cm [0.25 (0.21-0.37) vs 0.53 (0.37-0.61) arbitrary units, p<0.01]. Notably, tumor size was inversely correlated with STAT3 activities in T1799A BRAF mutation-positive cases (Rs=-0.58, p<0.05), but not mutation-negative cases. CONCLUSIONS: STAT3 activities of PTC measured via DNA binding are suppressed in contrast to other human cancers. Tumor size larger than 2 cm is the only clinicopathologic parameter associated with low STAT3 activity. Moreover, tumor size appears inversely correlated with STAT3 activity, specifically in T1799A BRAF mutation-positive cases.

Prevalence of echocardiographic criteria for the diagnosis of pulmonary hypertension in patients with Graves' disease: before and after antithyroid treatment.

BACKGROUND: Right-sided heart failure with clinical manifestation is only occasionally seen in patients with Graves' disease (GD). Recent studies revealed that pulmonary hypertension (PHT) detected by echocardiography was not rare in patients with GD. We performed this study to investigate the prevalence of PHT in patients with GD before and after antithyroid treatment, and to assess potential mechanisms from the relationship with clinical and echocardiographic features. SUBJECTS AND METHODS: Serial echocardiographic examinations were performed in 64 patients with newly diagnosed GD before and after antithyroid treatment to measure cardiac factors, such as pulmonary artery systolic pressure (PAPs), cardiac output, total vascular resistance, left ventricular filling pressure and right ventricular (RV) function. PHT was defined as PAPs of at least 35 mmHg. RESULTS: The prevalence of PHT in untreated GD patients was 44% (28 out of 64 patients). The presence of systemic hypertension was associated with PHT, especially with pulmonary venous hypertension. GD patients with PHT showed reduced RV function represented by higher RV myocardial performance index without difference of pulmonary vascular resistance, RV wall thickness and peak systolic velocity of free wall side of tricuspid annulus. Follow-up echocardiography was performed in 20 out of 28 GD patients with PHT, and PHT disappeared in all except one patient. CONCLUSION: PHT is a frequent and reversible complication in patients with GD. Our study suggests that PHT in GD may not be related to underlying autoimmune process and increased pulmonary blood flow from thyrotoxicosis might contributes to the pathogenesis of PHT related to GD.

The Role of Core Needle Biopsy and Its Impact on Surgical Management in Patients with Medullary Thyroid Cancer: Clinical Experience at 3 Medical Institutions.

BACKGROUND AND PURPOSE: Medullary thyroid carcinoma is an uncommon malignancy that is challenging to diagnose. Our aim was to present our experience using core needle biopsy for the diagnosis of medullary thyroid carcinoma compared with fine-needle aspiration. MATERIALS AND METHODS: Between January 2000 and March 2012, 202 thyroid nodules in 191 patients were diagnosed as medullary thyroid cancer by using sonography-guided fine-needle aspiration, core needle biopsy, or surgery. One hundred eighty-three thyroid nodules in 172 patients were included on the basis of the final diagnosis. We evaluated the sensitivity and positive predictive value of fine-needle aspiration and core needle biopsy for the diagnosis of medullary thyroid cancer. We compared the rate of a delayed diagnosis, a diagnostic surgery, and surgery with an incorrect diagnosis for fine-needle aspiration and core needle biopsy and investigated the factors related to the fine-needle aspiration misdiagnosis of medullary thyroid cancer. RESULTS: Fine-needle aspiration showed 43.8% sensitivity and 85.1% positive predictive value for the diagnosis of medullary thyroid cancer; 25.7% (44/171) of patients had a delayed diagnosis, while 18.7% (32/171) underwent an operation for accurate diagnosis, and 20.5% (35/171) underwent an operation with an incorrect diagnosis. Core needle biopsy achieved 100% sensitivity and positive predictive value without a delay in diagnosis (0/22), the need for a diagnostic operation (0/22), or an operation for an incorrect diagnosis (0/22). A calcitonin level of <100 pg/mL was the only significant factor for predicting the fine-needle aspiration misdiagnosis of medullary thyroid cancer (P = .034). CONCLUSIONS: Core needle biopsy showed a superior sensitivity and positive predictive value to fine-needle aspiration and could optimize the surgical management in patients with medullary thyroid cancer. Because the ability of fine-needle aspiration to diagnose medullary thyroid cancer significantly decreases in patients with serum calcitonin levels of <100 pg/mL, core needle biopsy could be indicated for these patients to optimize their surgical management.

A strong association between thyrotropin receptor-blocking antibody-positive atrophic autoimmune thyroiditis and HLA-DR8 and HLA-DQB1*0302 in Koreans.

We investigated whether the associations between HLA alleles of patients with autoimmune hypothyroidism varied according to the presence or absence of TSH receptor-blocking antibody (TRBab). We analyzed the HLA-A, -B, -C, and -DR antigens by serotyping and the DQA1 and DQB1 genes using both enzymatic DNA amplification and sequence-specific oligonucleotide hybridizations. The patient population consisted of 47 Korean patients with atrophic autoimmune thyroiditis and 62 patients with goitrous autoimmune thyroiditis. The antigen frequency of HLA-DR8 was significantly increased in 23 atrophic autoimmune thyroiditis patients that were positive for TSH binding inhibitor immunoglobulin (TBII) compared to 136 controls [52% vs. 16%; chi 2 = 13.1; Pc (corrected P value) = 0.003]. This relative risk was 5.7; the etiological fraction was 0.43. HLA-DQB1*0302 was also increased in patients with TBII-positive atrophic autoimmune thyroiditis (24% vs. 7%; chi 2 = 11.2; Pc = 0.012; relative risk = 4.4; etiological fraction = 0.19). No specific DR antigens or DQB1 alleles were increased in either TBII-negative atrophic autoimmune thyroiditis or goitrous autoimmune thyroiditis. A significant decrease in the frequency of HLA-DR6 antigen was observed in both TBII-positive atrophic autoimmune thyroiditis (0% vs. 32%; chi 2 = 8.4; Pc = 0.03) and goitrous autoimmune thyroiditis (0% vs. 32%; chi 2 = 23.2; Pc < 0.001) patients. The frequency of the HLA-Cw1 antigen was significantly increased in all patient groups. We conclude that TRBab-positive atrophic autoimmune thyroiditis is immunogenetically different from both goitrous autoimmune thyroiditis and TRBab-negative atrophic autoimmune thyroiditis. It is possible that HLA-DR8 and/or DQB1*0302 may be related to the susceptibility genes involved in the production of TRBab in Koreans.

Paget bone disease involving young adults in 3 generations of a Korean family.

Although the etiology of Paget bone disease (PBD) is unknown, increasing evidence implicates a "slow virus" infection of the skeleton, perhaps in genetically predisposed individuals. PBD is rare in Asia. We describe a Korean family with PBD. The propositus noticed bowed limbs at approximately 25 years of age. Radiologic studies made when he was 55 years old revealed essentially panostotic PBD. Serum alkaline phosphatase (ALP) activity and osteocalcin (OC) levels were markedly elevated. An iliac crest specimen showed classic histopathologic changes of PBD. Additionally, palpable swellings were first observed at age 45 years at his occiput, pubic ramus, ileum, and facial bones. They contained numerous multinucleated cells and were originally diagnosed as giant cell tumors. However, we found that, like osteoclasts, these cells expressed considerable tartrate-resistant acid phosphatase activity. These "extraskeletal osteoclastomas" resolved rapidly with dexamethasone treatment. Two daughters, 20- and 24-years-of-age, were discovered by study of his 5 children to have elevated serum ALP activity and OC levels and widespread PBD. Both women, however, are without palpable masses and are asymptomatic. The propositus' father, who died at age 55 years, had similar skeletal deformities beginning at age 20 years, but was not examined. Leukocytopenia was found in the 3 living family members with PBD. There was no evidence for linkage of the PBD to HLA loci. The condition appears to be transmitted as an autosomal dominant trait and is manifest in young adult life. Multicentric extraskeletal osteoclastomas with remarkable sensitivity to dexamethasone treatment appear to be another unusual feature of this family's disorder. In this family, the stimulus for PBD is so great that the PBD is apparent at an early age, affects essentially the entire skeleton, and leads to the formation or extension of osteoclast-like cells into nonosseous tissues (extraskeletal osteoclastomas). This 3-generation kindred in Korea, where PBD is rare, shows a strong clustering of PBD compatible with autosomal dominant inheritance. Leukocytopenia appears to distinguish affected family members, but any role for this abnormality in the pathogenesis of PBD is unclear. Our findings support a heritable diathesis for PBD, perhaps mediated by an immune deficiency.

Thyroid hormone stimulates basal and interleukin (IL)-1-induced IL-6 production in human bone marrow stromal cells: a possible mediator of thyroid hormone-induced bone loss.

It is well known that excessive thyroid hormone in the body is associated with bone loss. However, the mechanism by which thyroid hormone affects bone turnover remains unclear. It has been shown that it stimulates osteoclastic bone resorption indirectly via unknown mediators secreted by osteoblasts. To determine if interleukin-6 (IL-6) or interleukin-11 (IL-11) could be the mediator(s) of thyroid hormone-induced bone loss, we studied the effects of 3,5,3'-tri-iodothyronine (T3) on basal and interleukin-1 (IL-1)-stimulated IL-6/IL-11 production in primary cultured human bone marrow stromal cells. T3 at 10(-12)-10(-8) M concentration significantly increased basal IL-6 production in a dose-dependent manner. It also had an additive effect on IL-1-stimulated IL-6 production, but failed to elicit a detectable effect on basal or IL-1-stimulated IL-11 production. Treatment with 17beta-estradiol (10(-8) M) did not affect the action of T3 on IL-6/IL-11 production. These results suggest that thyroid hormone may stimulate bone resorption by increasing basal and IL-1-induced IL-6 production from osteoblast-lineage cells, and these effects are independent of estrogen status.

Changes in thyrotropin receptor antibody after subtotal thyroidectomy in Graves' disease: comparison with the degree of lymphocytic infiltration in the thyroid.

To evaluate changes in TSH receptor antibody after surgery in Graves' disease and its relationship with the degree of lymphocytic infiltration, serial serum levels of TSH receptor antibody were measured before and after the subtotal thyroidectomy in 50 patients with Graves' disease. In 22 (44%) out of 50 patients, thyrotropin binding inhibitor immunoglobulin (TBII) levels gradually decreased and disappeared completely within 12 months after surgery (TBII disappearing group). Twenty-eight (56%) patients showed persistent TBII activity and their levels were not changed until 12 months after surgery (TBII persistent group). The changes of thyroid stimulating antibody (TSab) levels were very similar to those of TBII in both groups. The thyroidal lymphocytic infiltration was more prominent in the TBII disappearing group. The degree of the decrease of TBII levels after surgery correlated with the grade of thyroidal lymphocytic infiltration. There was no significant difference of TSH receptor antibody (both TBII and TSab) levels between the thyroid and peripheral venous blood. These data suggest that the persistence or disappearance of TSH receptor antibody after surgery may reflect the difference between patients in whom the thyroid is the major site of TSH receptor antibody and those in whom additional sites of TSH receptor antibody synthesis exist.

Diffuse striated muscle heteroplasia of the lung. An autopsy case.

We studied a diffuse, striated muscle heteroplasia in the lungs in a 20-week-old stillborn fetus. The lung was small, but retained normal shape. There was no tumefaction. Histologically, a massive and diffuse distribution of the striated muscle cells was found among the interstitia of the dysplastic lung, representing solid adenomatoid malformation. Based on the findings in this case and the cases of others, we believe that the presence of the striated muscle and adenomatoid malformation are causally related, and the striated muscle cells arise from the heteroplastic transformation of the pluripotential embryonal mesenchymal cells.

Collapsing benign cystic nodules of the thyroid gland: sonographic differentiation from papillary thyroid carcinoma.

BACKGROUND AND PURPOSE: The US features of benign and malignant nodules overlap, and benign thyroid lesions can mimic thyroid malignancy on US. Benign cystic nodules after spontaneous collapse or needle aspiration, can mimic malignant thyroid nodules. Our aim was to evaluate the US features of CBCNs of the thyroid that distinguish such nodules from malignant thyroid nodules. MATERIALS AND METHODS: US and clinical findings in 13 patients, each with a single CBCN, were evaluated to determine if they showed >50% cystic content on initial US or CT and >30% decrease in maximum diameter on follow-up US. We compared these findings with those of 26 patients, each with a single surgically confirmed PTMC. US scans were analyzed for internal content, shape, margin, echogenicity, presence of echogenic dots suggesting micro- and macrocalcification, inner isoechoic rim, and low-echoic halo. RESULTS: Six of the 13 (46%) CBCNs were classified as malignant on US due to their marked hypoechogenicity, microcalcification, or spiculated margins. US features that differed between CBCNs and PTMCs were shape (ovoid-to-round versus taller-than-wide, P = .016); margins (ill-defined versus spiculated, P < .000); low-echoic halo (P < .000); inner isoechoic rim (P < .000) with high negative predictive values (100%, 91%, 91%, and 89%, respectively); and clinically acceptable diagnostic accuracy (59%, 80%, 82%, and 85%, respectively). CONCLUSIONS: US features helpful for differential diagnosis of CBCNs from PTMCs include shape, margin, and the presence of an inner isoechoic rim and a low-echoic halo. Familiarity with US features suggesting CBCNs may be helpful in reducing unnecessary repeated FNABs.

Development of thyroid autoimmunity after administration of recombinant human interferon-alpha 2b for chronic viral hepatitis.

To investigate the frequency and clinical characteristics of autoantibody formation and development of autoimmune thyroid disease after interferon therapy, we measured the autoantibodies to thyrotropin receptor (TBII), thyroglobulin (ATA), and microsomal antigen (AMA) in 28 patients with histologically proven chronic viral hepatitis [25 males, three females; mean age 38.7 +/- 8.7 (SD) yr] receiving recombinant interferon-alpha 2b (IFN-alpha) treatment. Twenty patients with chronic hepatitis B (positive for HBsAg, HBeAg, and HBV DNA) and eight patients with chronic hepatitis C (positive for anti-HCV and HCV RNA) received IFN-alpha, 3 million units subcutaneously, three times a week for 6 months. Before, during, and up to 6 months after IFN-alpha therapy, thyroid hormone levels and titers of AMA, ATA, and TBII were measured every 2 months. None of them had thyroid dysfunction or antithyroid autoantibodies before IFN-alpha treatment. A 34-yr-old male patient developed Graves' disease during the last month of therapy. He required long-term antithyroid medications, even after discontinuation of IFN-alpha. Another 44-yr-old female patient developed AMA during IFN-alpha treatment; however, thyroid function remained normal and goiter did not develop in this patient. No other patient developed thyroid autoantibodies and thyroid dysfunction. In summary, only a small minority of patients will develop thyroid autoimmunity during IFN-alpha therapy, and much less often with this low dose of IFN-alpha.

Vitiligo in autoimmune thyroid disease.

The authors studied the association between vitiligo and autoimmune thyroid disease. Vitiligo was found in 20 of 293 patients with autoimmune thyroid disease (6.83%), 2 out of 227 patients with nonautoimmune thyroid disease (0.88%), and 3 out of 386 control group (0.78%). These results showed that vitiligo is closely associated with autoimmune thyroid disease (chi 2 = 24.33, p < 0.0001), but not with nonautoimmune thyroid disease. Prevalence of vitiligo in nonautoimmune thyroid disease was not different from that in control. Vitiligo in autoimmune thyroid disease was most frequently found on dorsum hands and forearms, and usually preceded the onset of thyroid disease. Four out of twenty patients with vitiligo associated autoimmune thyroid disease had another presumed autoimmune disease, that is, alopecia areata, alopecia totalis, and rheumatoid arthritis. These findings suggested that autoimmunity plays an important role in the pathogenesis of vitiligo.

Role of blocking TSH receptor antibodies on the development of hypothyroidism and thyroid atrophy in primary myxedema.

We studied blocking type TSH receptor antibodies in 28 patients with primary myxedema and 21 patients with goitrous Hashimoto's thyroiditis by measuring the ability of their IgG to inhibit TSH binding to its receptor, and to inhibit TSH-stimulated cAMP increases and 3H-thymidine incorporation in a rat thyroid cell line, FRTL-5. The incidences of TSH binding inhibitor immunoglobulin (TBII), thyroid stimulation blocking antibody (TSBAb) and thyroid growth blocking antibody (TGBAb) in patients with primary myxedema were 53.6%, 75% and 65.2%, respectively. However, in goitrous Hashimoto's thyroiditis, these were 14.3%, 0% and 17.7%, respectively. These antibodies inhibited the receptor binding of 125I-bTSH dose-dependently, and also inhibited dose-dependently not only TSH-stimulated but also Graves' IgG-stimulated cAMP increase and 3H-thymidine incorporation. TBII activities of patients with primary myxedema were significantly correlated with both their TSBAb (r = 0.665; p less than 0.01) and TGBAb (r = 0.618; p less than 0.01) activities. Thirteen patients whose TBII activities were more than 50% had both strong TSBAb (75.1-100%) and TGBAb (57.4-100%) activities. Transient neonatal hypothyroidism was found in an infant born to a mother having potent TBII activities. Serum of the baby also had potent TBII activities and the baby's IgG inhibited TSH-stimulated cAMP increase and 3H-thymidine incorporation. These data suggest that a significant proportion of patients with primary myxedema have potent blocking type TSH receptor antibodies. These might play a role in primary myxedema causing hypothyroidism and thyroid atrophy through inhibition of TSH-stimulated cAMP generation.

Pathogenetic role of thyrotropin receptor antibody in the development of hyperthyroidism following primary hypothyroidism.

The authors measured thyrotropin binding inhibitory immunoglobulin (TBII), thyroid stimulating antibody (TSAb), and thyroid stimulation blocking antibody (TSBAb) sequentially in patients who developed hyperthyroidism following primary hypothyroidism, and compared changes in these various functional parameters of thyrotropin receptor antibody (TRAb) with clinical manifestations, in order to investigate the role of TRAb in the development of hyperthyroidism following primary hypothyroidism. In a patient with goitrous chronic thyroiditis, TBII, TSAb and TSBAb were not detected at the initial hypothyroid phase. But with appearance of TBII and TSAb, the patient developed hyperthyroidism. In a patient with primary nongoitrous myxedema, initially high TBII and TSBAb were detected without TSAb activity. His TSBAb disappeared and TSAb appeared with development of goiter growth and hyperthyroidism. These two mechanisms, that is, appearance of previously absent TSAb and conversion of TSBAb to TSAb, might play a causative role in the development of hyperthyroidism following primary hypothyroidism. These phenomena might be evidence that Graves' disease, chronic thyroiditis, and primary nongoitrous myxedema are on a continuing spectrum of a common syndrome sharing similar pathophysiology, at least with respect to TRAb.

Graves' hyperthyroidism following primary hypothyroidism: sequential changes in various activities of thyrotropin receptor antibodies.

A 40-year-old male who developed Graves' hyperthyroidism following primary hypothyroidism is reported. He presented with clinical signs of hypothyroidism and concomitant myasthenia gravis. The thyroid was not palpable. He was treated with T4, pyridostigmine and prednisolone. One year later he developed hyperthyroidism and goitre. His initial serum IgG had no intrinsic thyroid stimulating activity, but showed almost complete inhibition of TSH-stimulated cAMP generation (99.4%, normal less than 38%) and [3H]thymidine incorporation (99.5%, normal less than 40%) into rat thyroid cells, FRTL-5 cells, with very high activity (80.2%, normal less than 15%) of TSH binding inhibitor immunoglobulin. When he developed hyperthyroidism and goitre, his IgG showed a strong thyroid stimulation, both cAMP production (27-fold increase) and [3H]thymidine incorporation (5.5-fold increase). No inhibitory activities were noted. These findings suggest that clinical states of autoimmune thyroid diseases can be changed in accordance with changes of functional properties of TSH receptor antibodies.

Anti-bovine TSH antibodies in patients with Graves' disease and primary myxedema.

Three patients with Graves' disease and one patients with primary myxedema had serum TSH-binding immunoglobulins of high affinity detected by the TSH binding inhibition immunoglobulin (TBII) assay. These IgGs bound 61%, 33%, 60% and 53% of radiolabeled TSH, respectively, higher than the maximal specific binding (25%) in the TBII assay. Such binding was detected even in the absence of TSH receptor with only small differences in the precipitable radioactivity (61%, 28%, 61%, 54%, respectively, in comparison with the assay non-specific binding 11.3%). The 125I-bTSH binding of IgGs was competitively inhibited by the addition of bTSH, but not inhibited by hTSH. Moreover IgG binding to bTSH was not inhibited by the addition of serial dilutions of TBII positive pooled Graves' IgG (0.1-10 mg/ml) from different untreated patients. The titers of these TSH binding antibodies were not changed during the treatment of Graves' disease. Following guinea pig fat cell membrane receptor purification, the IgG of one patient with Graves' disease revealed TBII activity of 43.7% inhibition of 125I-bTSH binding to the TSH receptor without binding activity of 125I-bTSH in the absence of the TSH receptor. These studies suggest that anti-TSH antibodies and TSH receptor antibodies are present independent of one another in sera of some patients with autoimmune thyroid diseases and anti-TSH antibodies result in false TBII assay results.

Transient neonatal hypothyroidism due to transplacental transfer of maternal immunoglobulins that inhibit TSH binding, TSH-induced cAMP increase and cell growth.

Transient neonatal hypothyroidism due to transplacental transfer of maternal blocking type TSH receptor antibodies (TRAb) was found in a baby born to a 27-yr-old mother, who had been receiving thyroxine medication for primary myxedema. Maternal IgG inhibited radiolabelled TSH binding to its receptor (TBII), TSH-stimulated thyroid adenylate cyclase (AC) activation (TSII) and TSH-stimulated 3H-thymidine uptake (TGII) in cultured rat thyroid cells (FRTL-5). At birth, the baby's IgG showed similar activities to maternal IgG but all these activities decreased gradually, and disappeared from her serum within 12 weeks of age. In the baby, initially nonvisualized thyroid was clearly visualized on 99 m-Tc thyroid scintigraphy when all these blocking activities disappeared, TSII and TGII being decreased more slowly than TBII, and the baby remained euthyroid after discontinuation of thyroxine. This study suggests that such IgGs induced hypothyroidism and thyroid atrophy in the mother and were responsible for transient neonatal hypothyroidism in the baby.

Inhibition of thyrotropin-stimulated adenylate cyclase activation and growth of rat thyroid cells, FRTL-5, by immunoglobulin G from patients with primary myxedema: comparison with activities of thyrotropin-binding inhibitor immunoglobulins.

We studied the blocking type TSH receptor antibodies in 28 patients with primary myxedema and 21 patients with goitrous Hashimoto's thyroiditis by measuring the ability of their IgGs to inhibit TSH binding to its receptor, and to inhibit TSH-stimulated cAMP increase and [3H]thymidine incorporation in a rat thyroid cell line, FRTL-5. The incidences of TSH binding inhibitor immunoglobulin, thyroid stimulation inhibiting immunoglobulin and thyroid growth inhibiting immunoglobulin in patients with primary myxedema were 54.6, 75 and 65.2%, respectively, against 14.3, 0 and 17.7%, respectively, in goitrous Hashimoto's thyroiditis. The antibodies inhibited dose-dependently not only TSH stimulated but also Graves' IgG-stimulated cAMP increase and [3H]thymidine incorporation. The TSH binding inhibitor immunoglobulin activities in patients with primary myxedema were significantly correlated with both the thyroid stimulation inhibiting immunoglobulin (r = 0.665; P less than 0.01) and the thyroid growth inhibiting immunoglobulin (r = 0.618; P less than 0.01) activity. Thirteen patients whose TSH binding inhibitor immunoglobulin activities were more than 50% had both strong thyroid stimulation inhibiting immunoglobulin (75.1-100%) and thyroid growth inhibiting immunoglobulin (57.4-100%) activities. These data suggest that the vast majority of patients with primary myxedema have potent blocking type TSH receptor antibodies. These might play a role in primary myxedema causing hypothyroidism and thyroid atrophy through inhibiting TSH-stimulated cAMP generation.

Nesidioblastosis in an adult with hyperinsulinemic hypoglycemia.

A 50-year-old Korean man with repeated episodes of temporary loss of consciousness was diagnosed as having hyperinsulinemic hypoglycemia. Under the tentative diagnosis of insulinoma, localization procedures were carried out but no tumor was found. By percutaneous transhepatic portal venous sampling, no definite gradient in insulin concentration was found. During exploratory laparotomy no tumor was palpable in the pancreas, and intraoperative ultrasonography showed low echogenicity in the pancreatic head. Whipple's operation was performed and 70% of the proximal pancreas was removed. Histomorphometric examination of the resected specimen revealed graded hyperplasia of the islet cells. The most profuse hyperplasia was noted in the head with progressive decrease in the degree of hyperplasia to the body and tail. The patient remains euglycemic and tolerates 24 h fasting without any medication until 15 months after operation.