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A patient with underlying Hashimoto's thyroiditis developed amiodarone-induced thyrotoxicosis type 1 that was successfully treated using methimazole in combination with potassium iodide. A 35-year-old woman admitted for perinatal care of twin-to-twin transfusion syndrome was given amiodarone for 7 days for paroxysmal ventricular contraction following pulseless ventricular tachycardia 1 day after delivery. She developed thyrotoxicosis one month after the discontinuation of amiodarone therapy and was negative for thyroid-stimulating hormone receptor antibody. An increased peak velocity of the superior thyroid artery suggested amiodarone-induced thyrotoxicosis type 1. Her thyroid function recovered after combination therapy with methimazole and potassium iodide.

Background Major symptoms of progressive chronic kidney disease (CKD) are similar to those of hypothyroidism. Hidden symptoms of hypothyroidism underlying CKD are often observed in clinical practice. This study aimed to ascertain the frequency of hypothyroidism complicated by CKD, and to analyze factors impacting thyroid function. Methods During the period from April 2012 through October 2016, 510 CKD patients at our outpatient clinic were measured thyroid and kidney function for diagnosing hypothyroidism (overt hypothyroidism, OH; subclinical hypothyroidism, SH; non-thyroidal illness, NTI) and evaluating the stage of CKD. All patients were over 15 years of age. Results There were significant differences in age, estimated glomerular filtration rate (eGFR), urinary protein (UP), and serum albumin (Alb) among patients with OH, SH, and NTI compared to the normal group in univariate and multivariate analyses. UP showed the highest odds ratio of OH, SH, and NTI but no differences were recognized in gender in each group. Frequency distribution showed that the prevalence of thyroid dysfunction was greater among more severe stage of CKD with higher amount of UP. OH and SH did not show high positive ratio of anti-thyroglobulin antibody (TgAb) and anti-thyroid peroxidase antibody (TPOAb). NTI and normal subjects showed higher positive ratio as 50.0% and 42.9% of TgAb and TPOAb than OH and SH. Conclusions Hypothyroidism complicated by CKD exhibited a high prevalence. Age, eGFR, UP, and serum Alb were related to the prevalence of hypothyroidism, whereas gender was not and this was contradicted to the prevalence of hypothyroidism in general population. The prevalence of OH and SH was higher among patients with higher stage of CKD with increased UP. Hypothyroidism complicated by CKD may involve different onset mechanisms unrelated to antithyroid antibodies (ATAb). In CKD patients, assessments of OH and SH, as well as NTI, are needed for proper diagnosis.

After the Fukushima Daiichi nuclear accident in 2011 and thyroid examinations of children in Fukushima, the Radiation Medical Science Center began "Explanatory meetings on thyroid examination" as a method of communication with residents such as the subjects themselves and their guardians. Through questionnaires, we examined the relationship between anxiety (regarding the effects of radiation on the thyroid) before the meetings and individual attributes including attitudes on radiation, and then verified the effects of the meetings using measures of anxiety, comprehension, and satisfaction, as the outcomes. Of the meetings in 2014-2015, 799 people attended 30 sessions in Kenchu, Kenpoku, Iwaki, Soso, and outside of Fukushima Prefecture, and 594 people responded the questionnaires before and after the meetings on the same day. Level of anxiety before the meetings varied depending on individual attributes (including attitudes regarding collection information on radiation, advisors on radiation, and levels of subjective understanding), highlighting the importance of presenting information about radiation in a manner that is easy to understand, as well as providing opportunities for the exchange of opinions. Participation in meetings reduced anxiety. This was largely attributed to explanations about general characteristics of cancer and objective facts, including doses; status of the Chernobyl accident; and comparison in results of thyroid examinations with other prefectures in Japan. An opportunity for a question-and-answer session also contributed to increased overall satisfaction. The lower number of meeting participants was associated with anxiety reduction and higher subjective comprehension. The present findings obtained will be useful to facilitate evidence-based risk communication.

SummaryObjective Thyroid storm (TS) is a life-threatening endocrine emergency. This study aimed to achieve a better understanding of the management of TS by analyzing therapeutic modalities and prognoses reported by nationwide surveys performed in Japan. Design, patients and measurements Retrospective analyses were performed on clinical parameters, outcomes, and treatments in 356 TS patients. Results Patient disease severities assessed via Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores significantly correlated with mortality. Free triiodothyronine (FT3) and the FT3/free thyroxine (FT4) ratio inversely correlated with disease severity. Methimazole (MMI) was used in the majority of patients (78·1%), and there were no significant differences in mortality or disease severity between those treated with MMI and those receiving propylthiouracil (PTU). Patients who received inorganic iodide (KI) demonstrated higher disease severity but no change in mortality compared to those who did not. Patients treated with corticosteroids (CSs) demonstrated significantly higher disease severity and mortality than those who were not. Disease severity in patients treated with intravenous administration of beta-adrenergic antagonists (AAs) was significantly higher than those treated with oral preparations, although no significant difference in mortality was observed between these groups. In addition, mortality was significantly higher in patients treated with non-selective beta-AAs as compared with other types of beta-AAs. Conclusion In Japan, MMI was preferentially used in TS and showed no disadvantages compared to PTU. In severe TS, multimodal treatment, including administration of antithyroid drugs, KI, CSs and selective beta1-AAs may be preferable to improve outcomes.

Papillary thyroid carcinoma (PTC) is the most frequent thyroid carcinoma. PTC cell lines have been of considerable value in studying aspects of thyroid cancer, such as gene expression, cell proliferation, and differentiation. Here we report three novel PTC lines established from three patients with different backgrounds. Case 1 was a 38-year-old woman with PTC in the right thyroid lobe, with no metastasis. The cell line was established from the resection sample and named D-PTC. The cell line consisted of epithelial cells with few lysosomes and showed a pavement structure and follicular formation at confluency. There was a little pilling up. The secretion of free thyroxin (fT4) and thyroglobulin (Tg) was increased by TSH, or GH and IGF-I treatment. Case 2 was a 22-year-old woman with PTC initially in the right thyroid lobe, but 4 years after the right lobe resection, PTC metastasis was observed in left lobe. The cell line was established from a sample of the second resection and named UD-PTC. This cell line consisted of small epithelial cells with evident lysosomes and exhibited floating cell clusters. The secretion of fT4 and Tg was slightly increased by TSH, or GH and IGF-I treatment. Case 3 was an 85-year-old man with PTC and with acromegaly. Metastasis was observed at cervical lymph nodes. The cell line was derived from the metastasis region and named A-PTC. This cell line consisted of small epithelial cells and many lysosomes. The cells frequently showed pilling up. The secretion of fT4 and Tg was significantly increased by GH and IGF-I treatment. We have established three PTC cell lines with substantial variation in their phenotype. The cell lines may be useful for thyroid cancer research.

Thyroid storm is an endocrine emergency which is characterized by multiple organ failure due to severe thyrotoxicosis, often associated with triggering illnesses. Early suspicion, prompt diagnosis and intensive treatment will improve survival in thyroid storm patients. Because of its rarity and high mortality, prospective intervention studies for the treatment of thyroid storm are difficult to carry out. We, the Japan Thyroid Association and Japan Endocrine Society taskforce committee, previously developed new diagnostic criteria and conducted nationwide surveys for thyroid storm in Japan. Detailed analyses of clinical data from 356 patients revealed that the mortality in Japan was still high (∼11%) and that multiple organ failure and acute heart failure were common causes of death. In addition, multimodal treatment with antithyroid drugs, inorganic iodide, corticosteroids and beta-adrenergic antagonists has been suggested to improve mortality of these patients. Based on the evidence obtained by nationwide surveys and additional literature searches, we herein established clinical guidelines for the management of thyroid storm. The present guideline includes 15 recommendations for the treatment of thyrotoxicosis and organ failure in the central nervous system, cardiovascular system, and hepato-gastrointestinal tract, admission criteria for the intensive care unit, and prognostic evaluation. We also proposed preventive approaches to thyroid storm, roles of definitive therapy, and future prospective trial plans for the treatment of thyroid storm. We hope that this guideline will be useful for many physicians all over the world as well as in Japan in the management of thyroid storm and the improvement of its outcome.

OBJECTIVE: To analyze activities of adrenal steroidogenic enzymes in type 2 diabetes mellitus, serum levels of 11 steroid hormones were measured simultaneously. SUBJECTS: We studied 130 patients with type 2 diabetes mellitus (74 men and 56 women between the ages of 40 and 69 years), whose blood glucose control had been poor (more than 10% in HbA(1c)). Age-matched normal subjects served as the control group. METHODS: Serum levels of steroid hormones (pregnenolone (Preg), progesterone (Prog), deoxycorticosterone (DOC), corticosterone (B), 17-hydroxypregnenolone (17-OH-Preg), 17-hydroxyprogesterone (17-OHP), 11-deoxycortisol (S), cortisol (F), dehydroepiandrosterone (DHEA) and Delta4-androstenedione (Delta4A)) were measured by HPLC/RIA methods. Fasting plasma glucose (FPG), HbA(1c), ACTH, serum immunoreactive insulin (IRI) and DHEA sulfate (DHEA-S) were also measured. We analyzed product/precursor ratios to assess relative activities of adrenal steroidogenic enzymes. RESULTS: Serum levels of ACTH and F were high and DHEA and DHEA-S were low in both male and female patients under poor blood glucose control. Following 6-months treatment with diet only or with sulfonylurea, FPG and HbA(1c) improved, and blood concentrations of ACTH and F decreased while DHEA and DHEA-S levels increased to within the normal range. DHEA/17-OH-Preg and Delta4A/17-OHP ratios, reflecting 17,20-lyase activity, were low before treatment and recovered to the normal range after treatment, and 17-OH-Preg/Preg and 17-OHP/Prog ratios, reflecting 17-hydroxylase activity, were high before treatment, and fell within the normal range after treatment. 3beta-Hydroxysteroid dehydrogenase, 21-hydroxylase and 11beta-hydroxylase activities remained within the normal range both before and after treatment. CONCLUSIONS: These data suggest that the decrease in DHEA and DHEA-S concentrations together with the high F levels that occur in patients with type 2 diabetes mellitus is associated with low 17,20-lyase and high 17-hydroxylase activity in the adrenal steroidogenic enzymes. High insulin concentrations may further lower DHEA and DHEA-S levels.

Thyroid storm (TS) is life threatening. Its incidence is poorly defined, few series are available, and population-based diagnostic criteria have not been established. We surveyed TS in Japan, defined its characteristics, and formulated diagnostic criteria, FINAL-CRITERIA1 and FINAL-CRITERIA2, for two grades of TS, TS1, and TS2 respectively.We first developed diagnostic criteria based on 99 patients in the literature and 7 of our patients (LIT-CRITERIA1 for TS1 and LIT-CRITERIA2 for TS2). Thyrotoxicosis was a prerequisite for TS1 and TS2 as well as for combinations of the central nervous system manifestations, fever, tachycardia, congestive heart failure (CHF), and gastrointestinal (GI)/hepatic disturbances. We then conducted initial and follow-up surveys from 2004 through 2008, targeting all hospitals in Japan, with an eight-layered random extraction selection process to obtain and verify information on patients who met LIT-CRITERIA1 and LIT-CRITERIA2.We identified 282 patients with TS1 and 74 patients with TS2. Based on these data and information from the Ministry of Health, Labor, and Welfare of Japan, we estimated the incidence of TS in hospitalized patients in Japan to be 0.20 per 100,000 per year. Serum-free thyroxine and free triiodothyroine concentrations were similar among patients with TS in the literature, Japanese patients with TS1 or TS2, and a group of patients with thyrotoxicosis without TS (Tox-NoTS). The mortality rate was 11.0% in TS1, 9.5% in TS2, and 0% in Tox-NoTS patients. Multiple organ failure was the most common cause of death in TS1 and TS2, followed by CHF, respiratory failure, arrhythmia, disseminated intravascular coagulation, GI perforation, hypoxic brain syndrome, and sepsis. Glasgow Coma Scale results and blood urea nitrogen (BUN) were associated with irreversible damages in 22 survivors. The only change in our final diagnostic criteria for TS as compared with our initial criteria related to serum bilirubin concentration3 mg/dL.TS is still a life-threatening disorder with more than 10% mortality in Japan. We present newly formulated diagnostic criteria for TS and clarify its clinical features, prognosis, and incidence based on nationwide surveys in Japan. This information will help diagnose TS and in understanding the factors contributing to mortality and irreversible complications.

There are few case reports describing small cell lung carcinoma (SCLC), which secrete parathyroid hormone (PTH)-related protein (PTHrP) and result in hypercalcemia. We have established a novel cell line, derived from a 37-year-old woman with SCLC, which produced PTH, PTH-rP, and a part of proopiomelanocortin (POMC), and led to hypercalcemia. The cell line, named SS-1, was grown as floating cell clusters in DMEM/F12 medium supplemented with 10% fetal bovine serum and had a population doubling time of 72 h. The modal chromosome number was 47 (88%); marker chromosomes were not observed. The SS-1 cell line secreted not only PTHrP but also PTH, and both were decreased by CaCl(2) administration. Decreasing the concentration of Ca(++) in the growth medium stimulated the secretion of both PTHrP and PTH. The cell line had calcium sensing receptor (Cas-R). Since PTHrP and PTH secretion from the SS-1 cells was related to Ca(++) concentration in the growth medium, the cell line might be useful for the study of PTH-rP and PTH regulation as well as for SCLC analysis. In addition, the cells secreted N terminal POMC, the precursor of adrenocorticotropic hormone, in response to stimulation with corticotropin releasing hormone. In summary, we established a novel cell line, SS-1 from SCLC, which produced PTHrP, PTH and N terminal POMC.

We have evaluated the role of circulating serum immunoglobulins (IgG) which inhibit the growth of thyroid in the etiology of thyroid atrophy in endemic cretinism. Twenty nongoitrous cretins (13 women and 7 men, age range: 9-33) were classified on the basis of clinical criteria for cretinism in China. They were born and living in an iodine deficient area, Xinjiang, northwest China. Antimicrosomal antibody titers were negative in all serum. Nine patients (seven women and two men; age range: 11-23) were biologically primary hypothyroid. Seven subjects were of a myxedematous form and two subjects were of a mixed form. We have studied thyroid-growth inhibiting immunoglobulin (TGII) activity that was measured as an inhibitory effect of 4 mg/ml IgG on TSH-induced [3H]-thymidine incorporation into the DNA of a rat thyroid follicular cell line, FRTL5 cells. Six (five women and one man) out of the nine patients with primary hypothyroidism (66.7 percent) had TGII. We also measured other growth-blocking IgG that inhibited [3H]-thymidine incorporation into DNA stimulated by insulin-like growth factor-I (IGF-I), a growth factor working through a cAMP-independent pathway. Five (three women and two men) out of nine patients (55.6 percent) with nongoitrous primary hypothyroidism had IGF-I-blocking IgG. These results indicate that TGII plays an important role in atrophy of the thyroid in spite of increased serum TSH concentrations, and IgG which inhibits thyroid growth stimulated by IGF-I also might play a role in thyroid atrophy in some endemic cretins.(ABSTRACT TRUNCATED AT 250 WORDS)

The relation between the incidence of methimazole (methylmercaptoimidazole; MMI)-induced agranulocytosis and initial MMI dose was evaluated in a group of 514 patients with Graves' disease who were treated between 1995 and 2005. One hundred and forty-six (28.40%) patients had received an initial dose of 30 mg MMI and 277 (53.89%) patients had been treated with 15 mg MMI. Nine patients (1.75%) developed agranulocytosis due to MMI treatment. Six (4.11%) of 146 patients who received an initial dose of 30 mg MMI, two (4.54%) of 44 patients given an initial dose of 20 mg MMI, and one (0.36%) of 277 patients given an initial dose of 15 mg MMI developed agranulocytosis. There was a statistically significant difference in agranulocytosis incidence between patients receiving an initial dose of 30 mg MMI and those who received an initial dose of 15 mg. Although 8 (4.10%) of 195 patients in the high-dose group (20 mg or higher) developed agranulocytosis, only 1 (0.31%) of 319 patients in the low-dose group (15 mg or lower) did. In conclusion, the incidence of agranulocytosis with low-dose MMI therapy was ten times lower than that of the high-dose regimen.

This study was undertaken to clarify the status of the ACTH and cortisol responses to CRH in patients with white coat hypertension. White coat hypertension was defined as a difference between clinic blood pressure and ambulatory blood pressure of at least 20 mm Hg for systolic blood pressure and/or 10 mm Hg for diastolic blood pressure. CRH stimulation tests were performed between 1400 and 1700 h in 11 patients with white coat hypertension (4 males and 7 females) and 11 normal subjects (4 males and 7 females). Blood pressure and heart rate were measured 15 min before, at time zero, and 15, 30, 60, and 120 min after initiation of the CRH stimulation tests. In white coat hypertension, both the mean systolic blood pressure (162 15 mm Hg) and diastolic blood pressure (97 10 mm Hg) were higher than in controls (P < 0.01) on 3 occasions. The mean ambulatory blood pressure for the 24-h period of the test did not differ between patients with white coat hypertension and normal subjects. Basal levels of ACTH and cortisol did not differ between patients with white coat hypertension and control subjects. However, challenge with CRH elevated ACTH (30 min) and cortisol (30, 60, and 120 min) to levels higher than those in controls, with the net increase in both ACTH and cortisol being higher than that in controls over the study period (P < 0.01). These significant responses suggest that white coat hypertension is associated with hypothalamic-pituitary-adrenal hypersensitivity to stressors. (J Clin Endocrinol Metab 87: 3672–3675, 2002)

We report a case in which pituitary apoplexy developed shortly after an intravenous (i.v.) injection of luteinizing hormone-releasing hormone (LH-RH). A 56-year-old man with prolactin-producing pituitary tumor complained of severe headache, visual field loss and facial nerve palsy shortly after LH-RH test. Magnetic resonance image (MRI) revealed a hemorrhage in the pituitary adenoma. He showed dramatic improvement in his symptoms after decompression surgery. These findings suggest a causal relationship between the i.v. injection of LH-RH and pituitary apoplexy. Possible pituitary apoplexy should be kept in mind during pituitary testing.

Most gastroenteropancreatic neuroendocrine tumors contain high-affinity binding sites for somatostatin, and somatostatin-receptor scintigraphy has been introduced for the in-vivo evaluation of such tumors. We report two patients with gastroenteropancreatic neuroendocrine tumors, in whom it was quite difficult to localize the tumors by conventional techniques, and in whom we found that (111)In-DTPA-pentetreotide scintigraphy was useful for accurate information on tumor localization. In the first patient, who had gastrinoma, multiple tumors were shown in the gastrinoma triangle, but we could not clarify whether there were any tumors in the pancreatic body. The selective arterial secretin injection (SASI) test diagnosed that the gastroduodenal artery was the feeder of the gastrinomas, and (111)In-DTPA-pentetreotide scintigraphy with single-photon emission computed tomography indicated the absence of tumors in the pancreatic body. In the second patient, who had insulinoma, multiple liver tumors and a large mass in the hilum of the spleen were shown. (111)In-DTPA-pentetreotide scintigraphy was useful in determining that there was no secretion of insulin from the tumor in the hilum of the spleen. In conclusion, X-ray computed tomography is superior for detection of neuroendocrine tumors, because not all neuroendocrine tumors have somatostatin receptors; however, somatostatin receptor scanning, as well as the SASI test, may be useful for the surveillance of patients with known primary tumors, for monitoring patients with disseminated disease, and for following the treatment of these patients.

To survey the prognoses of interferon-alpha (IFNα)-induced thyroid dysfunction, a total of 100 patients (49 males and 51 females) with biopsy-proven chronic active hepatitis C were studied. Either during or after IFNα therapy, 29 patients (33.7 %) revealed suppression/elevation of thyroid stimulating hormone (TSH) or both, transient thyrotoxicosis (TSH less than 0.1 μU/ml) or transient hypothyroidism (TSH 5.0-190.95 μU/ml). However, the thyroid function normalized without supplementation of the thyroid hormone in the follow-up period. In the same period, one of the 14 control patients (7.1 %) developed thyroid dysfunction. Thyroid abnormalities developed significantly more in patients with IFNα therapy than in those without IFNα therapy. The findings suggest that the occult autoimmune disorder becomes overt with IFNαtreatment in patients with pre-existent autoimmune thyroid disease. IFNα-induced thyroid dysfunction is transient, reversible and self-limited. It is not necessary to discontinue IFNα therapy when thyroid dysfunction develops.(Internal Medicine 37: 27-31, 1998)

A 28-year-old female with a 12-year history of goiter is presented. She had both clinical and laboratory evidence of hyperthyroidism, and her serum TSH was persistently and markedly elevated after treatment with antithyroid drugs. A TRH stimulation test resulted in no further rise in serum TSH after cessation of medication. Menses were regular and serum prolactin levels were normal. Serum LH and FSH responses to LHRH stimulation test were normal. No other evidence of pituitary or peripheral endocrine deficiencies existed. She underwent a subtotal thyroidectomy followed by 131I therapy three years later. A pituitary adenoma with sphenoidal and suprasellar extension was completely removed by transphenoidal approach. On light microscopy, it was mostly composed of chromophobic cells with occasional calcification showing sinusoidal pattern. On electron microscopy, most of the cells contained fine granules, which suggested thyrotroph. The immunoperoxidase technique revealed TSH beta in the cytoplasm of some adenoma cells. Three days postoperatively the patient's serum TSH levels returned to normal. TRH stimulation test produced a normal response in serum TSH. The patient was diagnosed hypothyroid by laboratory findings and is currently on thyroid replacement therapy. The patient became pregnant and delivered twice prior to the operation for pituitary adenoma. The previously reported TSH secreting adenomas associated with hyperthyroidism were reviewed.

Monolayer cultures of human thyroid cells derived from thyroid adenoma were utilized for the assay of thyroid stimulating substances such as thyrotropin (TSH), cholera toxin and thyroid stimulating immunoglobulin (TSI) in patients with Graves' disease. Adenoma cells were treated with 0.1% collagenase or 2000 unit/ml dispase to thyrocytes. The cells were cultured in MEM containing 10% fetal calf serum under an atmosphere of 5% CO2 in air. Within 24 hours, the cells attached themselves to the plastic surface and formed a monolayer. Cyclic AMP responses to TSH, cholera toxin or Graves' IgG were tested in a medium (PBS) containing 0.5 mM IBMX. The cyclic AMP responses to TSH were generally maximal on the 3rd day of culture and declined thereafter. The response was dose-dependent, and 10 microU/ml of TSH produced a significant increase of cellular cyclic AMP. The response by 1 microU/ml of TSH was 28 approximately 57 fold above the basal. The response was also a function of the incubation period. The maximal response was attained after 1 h incubation. When the cultures were washed after exposure to TSH, the cellular cyclic AMP levels rapidly declined, suggesting that removal of receptor-bound TSH results in a prompt cessation of cyclic AMP production. The thyroid cells in monolayer also responded to cholera toxin. The response was dose-dependent, and cholera toxin as low as 1 ng/ml was able to increase cyclic AMP production. In contrast to the observations in TSH, the cyclic AMP responses induced by cholera were hardly affected by washing the cultures after exposure to cholera toxin. Treatment of the cells with cholera toxin for only 3 min resulted in a continuous stimulation of cyclic AMP production for more than 4 hours. Confirming recent observations by others, most of Graves' IgG stimulated cyclic AMP production in a dose-dependent manner, but some of them inhibited the response at high concentrations. IgG derived from normal subjects did not increase cellular cyclic AMP. The time course in the cyclic AMP responses induced by Graves' IgG was variable among the IgG preparations from different patients. In some patients, the maximal responses were attained after 4 hours of incubation. A significant difference was noted between TSH and Graves' IgG in the stimulation of cyclic AMP production after washing the cultures. When the cultures were treated with Graves' IgG for 30 min, washed and then incubated without Graves' IgG, cellular cyclic AMP levels remained at the levels which were almost equivalent to those observed in the continuous presence of the IgGs.(ABSTRACT TRUNCATED AT 400 WORDS)