There is a great deal of research interest regarding the underlying causes of slightly elevated TSH values in patients with subclinical hypothyroidism (SH) without abnormal findings on ultrasonography or anti-thyroid antibodies. Twelve infertile women with thyroglobulin antibody (TGAb) and thyroid peroxidase antibody (TPOAb)-negative nongoitrous SH were referred to our department of endocrinology between September 2007 and September 2015. None had been diagnosed with autoimmune thyroid disease or had any possible causes of SH. In all cases, LT4 was prescribed to bring TSH value below 2.5 mIU/L. Among those with infertility treatments, six (50%) became pregnant and gave birth to infants. Here, we report three of these six women who successfully became pregnant with infertility treatments and were found to have thyroid autoimmunity on data obtained during the postpartum period. Two developed postpartum thyroiditis, and the remaining one woman was temporarily weakly positive for TPOAb at 9 months postpartum. We describe three infertile subclinically hypothyroid women without goiter or anti-thyroid antibodies with potential thyroid autoimmunity. Thyroid autoimmunity is one of the most important issues for management of pregnant women, and thus, our findings are noteworthy for the care of infertile women with SH. This report provides valuable insights into the presence of autoimmunity in nongoitrous thyroid-associated antibody-negative SH patients.
Glucose intolerance is often observed in patients with pheochromocytoma. However, it remains controversial issue that glucose intolerance on pheochromocytoma is caused by impaired insulin secretion and/or by increased insulin resistance. We aimed to reveal the mechanism of glucose intolerance on pheochromocytoma with regard to the type and amount of catecholamines released. We evaluated 12 individuals diagnosed with pheochromocytoma and who underwent surgery to remove it. We examined glycemic parameters before and after surgery and investigated the association between the change of parameters of insulin secretion (homeostasis model assessment of beta-cell function (HOMA-beta)), insulin resistance (homeostasis model assessment of insulin resistance (HOMA-IR)) and that of urinary levels of metanephrine/normetanephrine before and after surgery. Overall, fasting plasma glucose, glycated hemoglobin (HbA1c), HOMA-beta, and HOMA-IR were improved significantly after surgery. Regression analysis showed that the improvement in HOMA-beta from before to after surgery was significantly positively associated with an improvement in urinary levels of metanephrine from before to after surgery and showed a significantly negative association with improvement in urinary levels of normetanephrine from before to after surgery. The improvement in HOMA-IR from before to after surgery was significantly positively associated with an improvement in urinary levels of normetanephrine from before to after surgery. Our results showed that pheochromocytoma extirpation improved glycemic parameters. Furthermore, the different effects elicited by excess amounts of adrenaline and noradrenaline on glucose intolerance were demonstrated.
The extent of thyroidectomy in Graves' disease remains controversial. In our institution, long-term euthyroidism without thyroxin replacement therapy has been the aim, and it has long been the standard surgical procedure used to treat Graves' disease in many institutions, including our hospital. Based our several clinical studies, it was concluded that subtotal thyroidectomy is not suitable as a standard surgical procedure for the treatment of Graves' disease. In 2009, the surgical strategy for Graves' disease was changed from subtotal thyroidectomy to total thyroidectomy in our hospital. In this study, how surgical complications have changed after this modification was examined. The subjects were 1,476 patients with Graves' disease treated by thyroidectomy between 2006 and 2014. There were 1,119 females and 357 males with a median age of 39 years. A total of 660 patients underwent bilateral subtotal thyroidectomy (ST group), and 816 patients underwent total thyroidectomy (TT group). Both transient hypocalcemia and prolonged hypocalcemia were observed significantly more frequently in the TT group than in the ST group (p < 0.001). Total thyroidectomy was identified as risk factors for prolonged hypocalcemia on multivariate analysis. In conclusion, total thyroidectomy is a reliable and effective therapy for controlling hyperthyroidism in terms of controlling of hyperthyroidism. However, it should be noted that total thyroidectomy resulted in increased rate of prolonged hypocalcemia. Surgeons should try to reduce the surgical complication rate as much as possible.
Cushing's syndrome (CS) is a clinical syndrome characterized by hypercortisolemia. Cyclic Cushing's syndrome (CCS), which exhibits a periodic or irregular increasing pattern in cortisol, is a rare type of Cushing's syndrome. A 37-yearold man came to our hospital because of repeated dizzy spells, weakness and hypercortisolemia lasting two weeks. Endocrinological examinations indicated CCS with periodic and intermittent increases in cortisol. Enhanced computed tomography (CT) revealed space occupying lesions on the upper lobe of left lung, and biopsy eventually proved that these were pulmonary carcinoid tumors with ectopic ACTH secretion, which was subsequently manifested a Cushing's syndrome. PET-CT, ultrasound and biopsy of the thyroid gland indicated bilateral thyroid papillary carcinoma. CT scan showed bilateral nodular hyperplasia of the adrenal gland. Enhanced magnetic resonance imaging (MRI) confirmed that the high signal disappeared on the posterior lobe of the pituitary gland and that the pituitary stalk shifted left, which was suspected to be nonfunctional pituitary microadenoma. The patient underwent surgery involving resection of the left upper pulmonary lobe and the mediastinal lymph node around the hilus pulmonis, which resulted in complete remission of CCS. The patient then chose elective surgery for the thyroid papillary carcinoma. An analysis of the patient's genomic DNA identified a novel mutation in PDE 11A: c.2032 (exon 12) G > A, which is associated with primary pigmented nodular adrenocortical disease (PPNAD). This is a novel mutation which has been no previous public clinical report on this mutation as it relates to this disease.
Surgical resection is the primary treatment strategy for pheochromocytoma; however, it carries a high risk of morbidity and mortality, especially with respect to cardiovascular complications, which is the most common kinds of morbidity. The risk factors for morbidity remain unclear and require further exploration, moreover no studies focus on risk factors for cardiovascular morbidity. Herein we identified the risk factors for cardiovascular morbidity after pheochromocytoma surgery in Chinese patients. We retrospectively reviewed 262 patients who underwent unilateral surgical resection of pheochromocytoma at our center between 1 January 2007 and 31 December 2016. Patient demographics and extensive perioperative data were recorded and evaluated. Adjusted odds ratios and 95% confidence intervals were determined by multivariate logistic regression. Cut-off values and the area under the curve for continuous risk factors were calculated based on receiver operating characteristic curve analysis. A p-value <0.05 was considered statistically significant. Of the 262 patients, 63 (24.0%) had cardiovascular morbidity. The independent risk factors for cardiovascular morbidity were low body mass index, large radiographic tumor size, coronary heart disease, no preoperative crystal/colloid administration, and intraoperative hemodynamic instability; the corresponding odds ratio were 0.762 (p < 0.001), 1.208 (p = 0.010), 2.378 (p = 0.012), 2.720 (p = 0.011), and 4.764 (p = 0.001), respectively. The optimal cut-off values for body mass index and radiographic tumor size were 24.59 kg/m(2) and 6.05 cm. We found that cardiovascular morbidity is common in patients after pheochromocytoma surgery. We identified five independent risk factors for cardiovascular morbidity. Identification of these risk factors may help to improve treatment strategies.
A functional link between clock gene expression and ovarian steroidogenesis was studied using human granulosa KGN cells. Similarities between changes in the mRNA and protein expression levels of Bmal1 and Clock and those of Per2 and Cry1 were found in KGN cells after treatment with forskolin. Among the interrelationships between the expression levels of clock and steroidogenic factors, Clock mRNA had a strongly positive correlation with P450arom and a negative correlation with 3 beta HSD. Knockdown of Clock gene by siRNA resulted in a significant reduction of estradiol production by inhibiting P450arom expression, while it induced a significant increase of progesterone production by upregulating 3 beta HSD in KGN cells treated with forskolin. Moreover, BMP-7 had an enhancing effect on the expression of Clock mRNA and protein in KGN cells. Thus, the expression levels of Clock, being upregulated by forskolin and BMP-7, were functionally linked to estradiol production and progesterone suppression by human granulosa cells.
Diazoxide is recognized as an effective medical treatment for insulinoma. However, due to its adverse effects, such as fluid retention, it is sometimes difficult to employ diazoxide at an effective dose in clinical practice. This study aimed to clarify the clinical factors, which may affect efficacy and safety of the diazoxide treatment. We retrospectively evaluated the medical records of 20 patients with insulinoma including 4 malignant cases. The patients were divided into two groups according to the presence or absence of favorable outcomes or adverse effects, and the clinical features of both groups were compared. Diazoxide was effective and ineffective in each 9 patients, respectively. In other 2 cases, the efficacy could not be determined. In the effective group, all patients had benign insulinoma. Additionally, the tumor size determined by imaging test was tended to smaller than the ineffective group but not statistically significant when malignant cases were excluded (p = 0.065). Fluid retention was observed more frequently in females than in males (p = 0.025). Five patients displayed unacceptable thrombocytopenia within a few weeks after the administration of diazoxide. In these patients, the diazoxide dose was significantly higher than that in the other patients [400 mg/day (250-500 mg/day) vs. 225 mg/day (50-425 mg/day), p = 0.027]. These findings may be informative in determining the indication and dose of diazoxide against insulinoma. In addition, a careful evaluation of platelet count would be required for a few weeks after the initiation of diazoxide treatment.
Concerning the needle size for thyroid fine needle aspiration cytology (FNAC), 25-27 -gauge needles are generally used in Western countries. However, in Japan, the use of larger needles (21-22-gauge needles) is common. The aim of our study was to determine the optimal needle size for thyroid FNAC. We performed ultrasound-guided FNAC for 200 thyroid nodules in 200 patients using two different-sized needles (22 and 25 gauge). For each nodule, two passes with the different-sized needles were performed. The order of needle sizes was reversed for the second group of 100 nodules. The second aspiration was more painful than the first, regardless of the needle size. An association with more severe blood contamination was more frequently observed with the use of 22 -gauge needles (32.0%) than with the use of 25-gauge needles (17.5%) and in the second aspiration (37.5%) than in the initial aspiration (12.0%). The initial aspiration samples were more cellular than the second aspiration samples. Regarding the unsatisfactory and malignancy detection rates. there was no statistical difference between the needles. In three of seven markedly calcified nodules, it was difficult to insert 25-gauge needles into the nodules. In terms of the diagnostic accuracy and pain, either needle size can be used. We recommend using 22-gauge needles for markedly calcified nodules because 25-gauge needles bend more easily in such cases. We demonstrated that the initial aspiration tended to obtain more cellular samples and to be less contaminated. Thus, the initial aspiration is more important and should be closely attended.
To explore new methods for intraoperative identification of parathyroid glands, 86 thyroid cancer patients, admitted to Xijing hospital from July 2017 to July 2018, were included. During lymph node dissection, parathyroid glands were firstly judged by clinician eyeballing, based on his clinical experience. Then, cytological detection was used for rapid identification via Diff-quik staining. PM monitoring was performed by PM detection kit. Finally, frozen pathology was examined and regarded as the golden standard. In this study, 172 suspicious parathyroid glands were observed. According to frozen pathology outcome, the accuracy, sensitivity and specificity of clinician eyeballing were calculated as 63.3%, 100%. and 13.9%. Kappa test showed poor consistency (kappa = 0.156), AUC area was 0.569 +/- 0.045, 95%CI = (0.480-0.658), p = 0.123. For cytological and PTH detection, the accuracy, sensitivity and specificity were 91.7% vs. 92.3%, 93.6% vs. 93.8% and 89.0% vs. 90.3%. Kappa value was 0.829 vs. 0.842, indicating good consistency. AUC area was 0.908 +/- 0.027 vs. 0.918 +/- 0.025, 95%CI = (0.856-0.960) vs. (0.869-0.966), p < 0.001, indicating higher diagnositic value. Besides, compared with frozen pathology, cytological detection was easily and rapid. The time-taking between frozen pathology and cytological detection or PTH detection were 39.0 +/- 6.59 min vs. 5.02 +/- 0.78 min and 39.0 +/- 6.59 min vs. 6.1 +/- 1.23 min, p < 0.001. In conclusion, intra-operative cytological detection maybe potential for in-situ preservation of parathyroid glands.
The revised Japan Association of Endocrine Surgeons (JAES)/Japanese Society of Thyroid Surgery (JSTS) guidelines for patients with papillary thyroid carcinoma (PTC) describe four risk classes: very-low-risk, low-risk, intermediate-risk, and high-risk. Here we conducted a retrospective analysis to evaluate the appropriateness of these guidelines' risk classification of PTCs. Lymph node recurrence-free, distant recurrence-free and cause-specific survivals at 15-year of high-risk group were significantly poorer than those at 15-year of intermediate-group and these survivals of intermediate-group were poorer than of low- or very-low-risk patients. In the subset analyses based on patient age (>= 55 years and <55 years), we obtained the same results in both subsets. Age significantly worsen the whole prognosis of high-risk patients and cause-specific survival of intermediate-risk patients, but not the prognosis of low- or very-low-risk patients. Therefore, the risk classification of the revised JAES/JSTS guidelines is appropriate, and therapeutic strategies should be decided based on the risk class together with the patients' age.
Adipose tissue harbors plasticity to adapt to environmental thermal changes. While brown adipocyte is a thermogenic cell which produces heat acutely in response to cold stimuli, beige (or brite) adipocyte is an inducible form of thermogenic adipocytes which emerges in the white adipose depots in response to chronic cold exposure. Such adaptability of adipocytes is regulated by epigenetic mechanisms. Among them, histone methylation is chemically stable and thus is an appropriate epigenetic mark for mediating cellular memory to induce and maintain the beige adipocyte characteristics. The enzymes that catalyze the methylation or demethylation of H3K27 and H3K9 regulate brown adipocyte biogenesis through their catalytic activity-dependent and - independent mechanisms. Resolving the bivalency of H3K4me3 and H3K27me3 as well as "opening" the chromatin structure by demethylation of H3K9 both mediate beige adipogenesis. In addition, it is recently reported that maintenance of beige adipocyte, beige-to-white transition, and cellular memory of prior cold exposure in beige adipocyte are also regulated by histone methylation. A further understanding of the epigenetic mechanism of beige adipocyte biogenesis would unravel the mechanism of the cellular memory of environmental stimuli and provide a novel therapeutics for the metabolic disorders such as obesity and diabetes that are influenced by environmental factors.
Soft-drink diabetic ketosis, characterized by acute onset ketosis induced by excessive ingestion of sugar-containing drinks, is often seen in obese, young patients, even with undiagnosed type 2 diabetes. We herein report a 15-year-old obese patient with the apolipoprotein E4/2 phenotype, in whom eruptive xanthomas lead to a diagnosis of soft-drink diabetic ketosis. He developed multiple asymptomatic yellowish papules on the auricles, back, buttocks and the extensor surfaces of the elbows and knees. He initially visited a dermatology clinic and his blood triglyceride and HbA1c levels were found to be 6,490 mg/di, and 16.5%, respectively. He was referred to our hospital for treatment of hyperglycemia and hypertyriglyceridemia. On admission, he had ketonuria and increased blood levels of 3-hydroxybutylate and acetoacetate. He habitually drank 1-3 litters of sweet beverages daily to quench his thirst. Therefore, "soft-drink diabetic ketosis" was diagnosed. Severe hypertriglyceridemia was considered to have been a consequence of impaired insulin action and his apolipoprotein E4/2 phenotype. We treated the diabetic ketosis and hypertriglyceridemia with intensive insulin therapy and a fat-restricted diet. At discharge, he no longer required insulin therapy and his blood glucose levels were controlled with metformin and voglibose. Along with amelioration of the hyperglycemia, triglyceride levels decreased to 247 ingidL without administration of anti-hyperlipidemia agents. The eruptive xanthoma lesions gradually diminished in size and number and eventually disappeared by 12 months. This case provides an instructive example of eruptive xanthomas serving as a sign of severe dysregulation, not only of lipid, but also glucose, metabolism.
Angiopoietin-like protein 8 (ANGPTL8) is a newly discovered adipokine plays an important role in energy homeostasis, obesity and type 2 diabetes (T2D). Although lifestyle modification in obesity and T2D is known to offer metabolic benefits, there is paucity of comprehensive data on change in ANGPTL8. We investigated the effect of lifestyle intervention on ANGPTL8 concentrations. 384 obese/overweight adults with newly diagnosed T2D were randomly assigned (1:1:1) to diet (n=128), diet + activity (n=128) or usual care (control, n=128) groups. All patients received usual care. Besides, the diet group received a calorie-restricted diet aiming for a weight loss of 5-10%. The diet + activity group additionally received a pedometer-based walling program. Primary outcome was change in ANGPTL8 concentration at 6 months. Data were analyzed according to intention-to-treat. From baseline to 6 months, the median ANGPTL8 level changed from 804.38 pg/mL to 792.86 pg/mL, in control group. Compared with control, ANGPTL8 decreased with diet (baseline-adjusted between-group difference was -121.00 pg/mL, 95% CI -177.47 to -64.53; p < 0.0001) and diet + activity (-126.16 pg/mL, -181.21 to -71.11; p < 0.0001). There was no greater effect of diet activity compared with diet (-5.16 pg/mL, -53.63 to 43.31; p= 0.8348). Both effects disappeared after adjusting for change in body fat, but did not differ significantly when adjusting for physical activity. A 6-month intervention inducing weight loss by a calorie-restricted diet or diet + activity, resulted in significant decrease on ANGPTL8 concentration. These effects were established by change in total body fat. and not by change in physical activity.
Premature ovarian insufficiency (POI) is a common endocrine disorder featured by the triad constituting of amenorrhea for at least four months, to date, the molecular pathogenesis of POI is largely undetermined. Despite several investigations have reported an increase in reactive oxygen species (ROS) content in idiopathic POI, the role of mitochondrial DNA (mtDNA) mutations/variants in the progression of POI has not been widely investigated. The current study aimed to explore the association between mt-tRNA mutations/variants and POI; we first used the PCR-Sanger sequencing to detect the mutations/variants in mt-tRNA genes from 50 POI patients and 30 healthy subjects. In addition, we evaluated the mitochondrial functions by using trans-mitochondrial cybrid cells containing these potential pathogenic mt-tRNA mutations. Consequently, five mutations: tRNA(Leu(UUR)) C3303T, tRNA(Met) A4435G, tRNA(Gln) T4363C, tRNA(Cys) G5821A and tRNA(Thr) A15951G were identified. Notably, these mutations occurred at the extremely conserved nucleotides of the corresponding mt-tRNAs and may result the failure in mt-tRNA metabolism and subsequently lead to the impairment in mitochondrial protein synthesis. Furthermore, biochemical and molecular analyses of the cybrid cells containing these mutations showed a significantly lower level of All' production when compared with the controls, whereas the ROS levels were much higher in POI patients carrying these mt-tRNA mutations, strongly indicated that these mt-tRNA mutations may cause the mitochondrial dysfunction, and play active roles in the progression and pathogensis of POI. Together, this study shaded additional light on the molecular mechanism of POI that was manifestated by mt-tRNA mutations.
This study assessed the association of muscle mass with insulin resistance, evaluated from the insulin sensitivity index (ISI), in Japanese patients with gestational diabetes mellitus (GDM). Consecutive patients with GDM (n= 96) admitted to St. Marianna University Hospital between October 2015 and March 2018 for initial education and glycemic control were enrolled in a prospective observational study. Insulin resistance was evaluated by measuring the ISI and body composition was assessed by bioelectrical impedance analysis. The subjects were aged 34.4 r 4.8 years (mean r SD) and their body mass index (BMI) before pregnancy was 22.3 :1, 4.0 kg/m(2). Fifty-three patients (55.2%) had a history' of diabetes in first-degree relatives. The ISI was 7.2 +/- 3.3, appendicular skeletal muscle mass (ASM) was 17.0 +/- 2.1 kg, and fat mass (FM) was 18.8 4, 8.2 kg. The ASM/FM ratio was 1.02 +/- 0.34. There was a positive correlation between FM and ASM (r= 0.734, p < 0.001). To adjust for confounders when evaluating the association of ASM with ISI, multivariate analysis was conducted using age, family history of diabetes, and BMI as variables. In this analysis, the ASM/FM ratio showed a significant positive correlation with ISI (beta= 0.303, p = 0.020). These findings suggest that inadequate ASM/FM ratio is important for the development of insulin resistance in Japanese patients with GDM. Excessive emphasis on dieting rather than health might increase the risk of GDM by reducing the muscle mass below the level that maintains normal glucose metabolism.