We characterize the clinical and laboratory characteristics of 5 patients with Graves’ thyrotoxicosis whose serum free thyroxine (fT4) concentration decreased unexpectedly to low levels on conventional doses of carbimazole (CMZ) therapy. The initial fT4 mean was 40.0 pM, range 25-69 pM. Thyroid volume by ultrasound measured as mean 11 ml, range 9.0-15.6 ml. Initial TSI levels measured 1487% to >4444%. Serum fT4 fell to low-normal or hypothyroid levels within 3.6 to 9.3 weeks of initiating CMZ 5 to 15 mg daily, and subsequently modulated by fine dosage adjustments. In one patient, serum fT4 fluctuated in a “yo-yo” pattern. There also emerged a pattern of low normal/low serum fT4 levels associated with discordant low/mid normal serum TSH levels respectively, at normal serum fT3 levels. The long-term daily-averaged CMZ maintenance dose ranged from 0.7 mg to 3.2 mg. Patients with newly diagnosed Graves' hyperthyroidism who have small thyroid glands and markedly elevated TSI titres appear to be “ATD dose sensitive.” Their TFT on ATD therapy may display a “central hypothyroid” pattern. We suggest finer CMZ dose titration at closer follow-up intervals to achieve biochemical euthyroidism.
carbimazole ; Thyroid Stimulating Immunoglobulin ; Immunoglobulins, Thyroid-Stimulating ; Immunologic Tests ; Graves disease

Antiepileptic drugs (AEDs) can induce severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome. We performed HLA genotyping and lymphocyte activation tests (LATs) for five AED-induced SCAR patients (three males and two females; aged 40–66 years old). Three patients were treated with carbamazepine (CBZ) for pain control, one was treated with phenytoin (PHT) for seizure prevention, and one was treated with valproic acid (VPA) for seizure prevention. One patient was diagnosed with CBZ-induced DRESS syndrome and the remaining patients were diagnosed with SJS. All patients recovered from SCARs after stopping suspicious drugs and supportive care. LATs were conducted to confirm the culprit drug responsible for inducing SCARs; and LAT results were positive for the suspected culprit drugs, in all except in one case. HLA-A,
Alleles ; Anticonvulsants ; Carbamazepine ; Cicatrix ; Drug Hypersensitivity Syndrome ; Female ; HLA-A Antigens ; Humans ; Long-Acting Thyroid Stimulator ; Lymphocyte Activation ; Lymphocytes ; Male ; Methods ; Phenytoin ; Seizures ; Stevens-Johnson Syndrome ; Valproic Acid

Most cases of congenital hyperthyroidism are autoimmune forms caused by maternal thyroid stimulating antibodies. Nonautoimmune forms of congenital hyperthyroidism caused by activating mutations of the thyrotropin receptor (TSHR) gene are rare. A woman gave birth to a boy during an emergency cesarean section at 33 weeks of gestation due to fetal tachycardia. On the 24th day of life, thyroid function tests were performed due to persistent tachycardia, and hyperthyroidism was confirmed. Auto-antibodies to TSHR, thyroid peroxidase, and thyroglobulin were not found. The patient was treated with propylthiouracil and propranolol, but hyperthyroidism was not well controlled. At 3 months of age, the patient had craniosynostosis and hydrocephalus, and underwent a ventriculoperitoneal shunt operation. Direct sequencing of the TSHR gene showed a heterozygous mutation of c.1899C>A (p.Asp633Glu) in exon 10. No mutations were discovered in any of the parents in a familial genetic study. We have reported a case of sporadic nonautoimmune congenital hyperthyroidism, by a missense mutation of the TSHR gene, for the first time in South Korea.
Cesarean Section ; Craniosynostoses ; Emergencies ; Exons ; Female ; Germ-Line Mutation ; Humans ; Hydrocephalus ; Hyperthyroidism* ; Immunoglobulins, Thyroid-Stimulating ; Iodide Peroxidase ; Korea ; Male ; Mutation, Missense ; Parents ; Parturition ; Pregnancy ; Propranolol ; Propylthiouracil ; Receptors, Thyrotropin ; Tachycardia ; Thyroglobulin ; Thyroid Function Tests ; Ventriculoperitoneal Shunt

PURPOSE: The aims of this study were to evaluate the expression of the large tumor suppressor (LATS) genes LATS1 and LATS2 by immunohistochemical staining of gastric cancer, and to evaluate the clinicopathological significance of LATS expression and its correlation with overall survival (OS). MATERIALS AND METHODS: LATS1 and LATS2 expression in a tissue microarray was detected by immunohistochemistry, using 264 gastric cancer specimens surgically resected between July 2006 and December 2009. RESULTS: Low expression of LATS1 was significantly associated with more advanced American Joint Committee on Cancer (AJCC) stage (P=0.001) and T stage (P=0.032), lymph node (LN) metastasis (P=0.040), perineural invasion (P=0.042), poor histologic grade (P=0.007), and diffuse-type histology by the Lauren classification (P=0.033). Low expression of LATS2 was significantly correlated with older age (≥65, P=0.027), more advanced AJCC stage (P=0.001) and T stage (P=0.001), LN metastasis (P=0.004), perineural invasion (P=0.004), poor histologic grade (P<0.001), and diffuse-type histology by the Lauren classification (P<0.001). Kaplan-Meier survival analysis revealed significantly poor OS rates in the groups with low LATS1 (P=0.037) and LATS2 (P=0.037) expression. CONCLUSIONS: Expression of LATS1 or LATS2 is a significant marker for a good prognosis in patients with gastric cancer.
Classification ; Genes, Tumor Suppressor ; Humans ; Immunohistochemistry ; Joints ; Long-Acting Thyroid Stimulator ; Lymph Nodes ; Neoplasm Metastasis ; Prognosis ; Stomach Neoplasms*

BACKGROUND: Selenium (Se) shows potential benefit in Graves' disease (GD) especially those with active Graves' ophthalmopathy(GO).  
OBJECTIVES: To evaluate the efficacy of Se supplementation among patients with GD and GO.
METHODOLOGY: We performed a meta-analysis of trials evaluating the efficacy of Se supplementation among adult patients with GD and active GO, versus either placebo or an alternative drug, and on top of standard therapy. Results were presented as mean differences, standard errors, and 95% confidence intervals,and graphically presented as forest plots.Estimates were calculated using the inverse variance method for continuous variables and pooled using the fixed effects model. I2 and Chi2 tests were used to assess heterogeneity.
RESULTS: Only  two  trials  were  ultimately  included  in  the  analysis. Both studies totaled 197 participants with GD and non-severe  GO  on  standard  therapy,  and  compared  Se  supplementation to placebo. The only common outcomes of  interest  were  changes  in  TSH  receptor  antibody  (TRAB)  and thyroid peroxidase antibody (TPOAB) titers. We found no statistically significant difference in either TRAB (95% CI,-1.38  [-3.19,  0.44],  p=0.14)  or  TPOAB  (95%  CI,  36.66  [-32.56, 105.88], p=0.30) titers between Se and placebo groups on follow  up.However,our analysis was limited by the small number of included studies, a small sample size, and lack of other synthesizable outcomes.
CONCLUSION: This is the  first  meta-analysis  summarizing  the available data on Se supplementation in patients with GD and  non-severe  GO.We found no statistically significant differences in both TRAB and TPOAB titers between Se and placebo groups. We recommend larger studies to validate these findings. 

Thyrotropin-binding Inhibitory Immunoglobulin ; Graves Ophthalmopathy ; Selenium ; Iodide Peroxidase ; Immunoglobulins, Thyroid-stimulating ; Graves Disease ; Thyroid Microsomal Antibodies ; Autoantibodies ; Forests ; Thyroid Gland

Background: Asians with Graves’ ophthalmopathy (GO) may have earlier compressive features due to narrower orbital apex and increased orbital volume. Objective: To determine the risk factors associated with activity and severity of GO among adults. Methodology: This was a cross-sectional analytical study of 163 adults with Graves’ disease (GD) from the outpatient clinics of the Philippine General Hospital. Demographics, clinical data, thyrotropin receptor antibody (TRAb) and urine iodine (UIE) levels were obtained. All participants were evaluated for activity and severity of GO by a single ophthalmologist. Results: The population was predominantly composed of females (81%) and nonsmokers (69%), with a mean age of 35 + 11 years and median GD duration of 2 years. Median TRAb was 8.9 U/L while UIE was 171 mcg/L. Eight percent exhibited active GO, with 85% having mild disease. Multivariate analysis showed male sex to be associated with severe disease (OR 3.71, p=0.041), while elevated TRAb was associated with both active (OR 1.03, p=0.002) and severe GO (OR 1.02, p=0.007). Conclusion Lower rates of active and severe GO were seen compared to previous reports. In this population of predominantly nonsmokers, elevated TRAb emerged as a risk factor for active and severe GO.
Graves Ophthalmopathy ; Graves Disease ; Long-Acting Thyroid Stimulator

Autoantibodies directed against the thyrotropin receptor have been well known to be an important pathogenesis of Graves' disease. However, the diagnosis and management of Graves' disease are still mainly dependent on thyroid function itself and clinical manifestation of thyrotoxic patients. That is mainly due to the low sensitivity of early generation of thyrotropin receptor assay methods. The development of sensitive thyrotropin receptor measuring tools through third generation immunometric assay made the diagnosis of Graves' disease with mild hyperthyroidism accurate and convenient for patients. Bioassay to detect thyroid stimulating immunoglobulin is also commercially available nowadays, which theoretically discriminate thyroid stimulating antibodies from thyrotropin receptor-blocking antibodies. Although the use of these serologic markers plays an informative role in accurately diagnosing Graves' disease and predicting the prognosis of disease, consideration of the heterogeneous nature of autoimmunity of Graves' disease and the limitation of indirect antibody assay is also required for proper management of Graves' disease patients. In this review, the clinical usefulness of thyrotropin receptor antibody in various clinical situations of Graves' disease was overviewed.
Antibodies ; Autoantibodies ; Autoimmunity ; Biological Assay ; Diagnosis ; Graves Disease ; Humans ; Hyperthyroidism ; Immunoglobulins, Thyroid-Stimulating ; Prognosis ; Receptors, Thyrotropin* ; Thyroid Gland ; Thyrotropin

BACKGROUND: Hyperthyroidism relapse in Graves disease after antithyroid drug (ATD) withdrawal is common; however, measuring the thyrotropin receptor antibody (TRAb) at ATD withdrawal in order to predict outcomes is controversial. This study compared measurement of thyroid stimulatory antibody (TSAb) and thyrotropin-binding inhibitory immunoglobulin (TBII) at ATD withdrawal to predict relapse. METHODS: This retrospective study enrolled patients with Graves disease who were treated with ATDs and whose serum thyroid-stimulating hormone levels were normal after receiving low-dose ATDs. ATD therapy was stopped irrespective of TRAb positivity after an additional 6 months of receiving the minimum dose of ATD therapy. Patients were followed using thyroid function tests and TSAb (TSAb group; n=35) or TBII (TBII group; n=39) every 3 to 6 months for 2 years after ATD withdrawal. RESULTS: Twenty-eight patients (38%) relapsed for a median follow-up of 21 months, and there were no differences in baseline clinical characteristics between groups. In the TSAb group, relapse was more common in patients with positive TSAb at ATD withdrawal (67%) than patients with negative TSAb (17%; P=0.007). Relapse-free survival was shorter in TSAb-positive patients. In the TBII group, there were no differences in the relapse rate and relapse-free survivals according to TBII positivity. For predicting Graves disease relapse, the sensitivity and specificity of TSAb were 63% and 83%, respectively, whereas those of TBII were 28% and 65%. CONCLUSION: TSAb at ATD withdrawal can predict the relapse of Graves hyperthyroidism, but TBII cannot. Measuring TSAb at ATD withdrawal can assist with clinical decisions making for patients with Graves disease.
Follow-Up Studies ; Graves Disease* ; Humans ; Hyperthyroidism ; Immunoglobulins ; Immunoglobulins, Thyroid-Stimulating* ; Prognosis ; Receptors, Thyrotropin ; Recurrence* ; Retrospective Studies ; Sensitivity and Specificity ; Thyroid Function Tests ; Thyroid Gland* ; Thyrotropin

PURPOSE: We aimed to investigate the predictive factors for early response to methimazole (MMI) in pediatric patients with Graves disease (GD). METHODS: Our study included 44 pediatric patients who were diagnosed with GD between January 1, 1993, and December 31, 2013, and were available for follow-up, achieving a normalization of thyroid functions (TFs) at the Chonbuk National University Hospital Pediatric Department. We retrospectively analyzed TFs such as tri-iodothyronine (T3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), and thyroid antibody levels at diagnosis. We also examined their family history of thyroid disease, symptoms at presentation, and normalization time for TF after treatment. We divided our clinical series of patients into the following 4 age groups: <7 years old, 7-12 years old, 13-15 years old, and 16-18 years old. RESULTS: At diagnosis, the time of normalization of T3 was significantly shorter in the higher antimicrosomal antibody (AMA) group compared with the lower AMA group (2.53 months vs. 6.18 months) (P<0.05). However, the time of normalization of T3/fT4/TSH had no significant correlations with other variables such as age, sex, a family history of thyroid diseases, thyroglobulin, thyroid-stimulating immunoglobulin, or antithyroglobulin antibody (ATA). CONCLUSION: Higher serological titers of AMA at diagnosis may have prognostic value in the response to initial MMI treatment in pediatric hyperthyroid GD patients.
Adolescent* ; Child* ; Diagnosis ; Follow-Up Studies ; Graves Disease* ; Humans ; Immunoglobulins, Thyroid-Stimulating ; Jeollabuk-do ; Methimazole* ; Retrospective Studies ; Thyroglobulin ; Thyroid Diseases ; Thyroid Gland ; Thyrotropin ; Thyroxine ; Triiodothyronine

PURPOSE: We aimed to investigate the predictive factors for early response to methimazole (MMI) in pediatric patients with Graves disease (GD). METHODS: Our study included 44 pediatric patients who were diagnosed with GD between January 1, 1993, and December 31, 2013, and were available for follow-up, achieving a normalization of thyroid functions (TFs) at the Chonbuk National University Hospital Pediatric Department. We retrospectively analyzed TFs such as tri-iodothyronine (T3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), and thyroid antibody levels at diagnosis. We also examined their family history of thyroid disease, symptoms at presentation, and normalization time for TF after treatment. We divided our clinical series of patients into the following 4 age groups: <7 years old, 7-12 years old, 13-15 years old, and 16-18 years old. RESULTS: At diagnosis, the time of normalization of T3 was significantly shorter in the higher antimicrosomal antibody (AMA) group compared with the lower AMA group (2.53 months vs. 6.18 months) (P<0.05). However, the time of normalization of T3/fT4/TSH had no significant correlations with other variables such as age, sex, a family history of thyroid diseases, thyroglobulin, thyroid-stimulating immunoglobulin, or antithyroglobulin antibody (ATA). CONCLUSION: Higher serological titers of AMA at diagnosis may have prognostic value in the response to initial MMI treatment in pediatric hyperthyroid GD patients.
Adolescent* ; Child* ; Diagnosis ; Follow-Up Studies ; Graves Disease* ; Humans ; Immunoglobulins, Thyroid-Stimulating ; Jeollabuk-do ; Methimazole* ; Retrospective Studies ; Thyroglobulin ; Thyroid Diseases ; Thyroid Gland ; Thyrotropin ; Thyroxine ; Triiodothyronine