Prospective Multicenter Registry-Based Study on Thyroid Storm: The Guidelines for the Management from Japan are Useful.

CONTEXT: The mortality rate in thyroid storm (TS) has been reported to be higher than 10%. OBJECTIVE: We aimed to evaluate the effectiveness of the 2016 guidelines for the management of TS proposed by the Japan Thyroid Association and Japan Endocrine Society. DESIGN: Prospective registry-based study through a secure web platform. SETTING: Prospective multicenter registry. PATIENTS AND MEASUREMENTS: Patients with new-onset TS were registered in the Research Electronic Data Capture (REDCap). On day 30 after admission, clinical information and prognosis of each patient were added to the platform. On day 180, the prognosis was described. RESULTS: This study included 110 patients with TS. The median of Acute Physiology and Chronic Health Evaluation (APACHE) II score was 13, higher than the score in the previous nationwide epidemiological study, 10 (p = 0.001). Nonetheless, the mortality rate at day 30 was 5.5%, approximately half compared with 10.7% in the previous nationwide survey. Lower body mass index, shock and lower left ventricular ejection fraction were positively associated with poor prognosis at day 30, while the lack of fever ≥ 38℃ was related to the outcome. The mortality rate in patients with an APACHE II score ≥12 for whom the guidelines were not followed was significantly higher than the rate in patients for whom the guidelines were followed (50% vs. 4.7%) (p = 0.01). CONCLUSIONS: Prognosis seemed better than in the previous nationwide survey, even though disease severity was higher. The mortality rate was lower when the guidelines were followed. Thus, the guidelines are useful for managing TS.

SFPQ associated with a co-activator for PPARγ, HELZ2, regulates key nuclear factors for adipocyte differentiation.

We recently isolated a novel co-activator of peroxisome proliferator-activated receptor γ, helicase with zinc finger 2 (HELZ2). HELZ2 null mice were resistant to diet-induced obesity and NAFFL/NASH, and HELZ2 was phosphorylated at tyrosine residues. In order to find a factor related to HELZ2, we analyzed products co-immunoprecipitated with phosphorylated HELZ2 by mass spectrometry analyses. We identified proline- and glutamine-rich (SFPQ) as a protein associating with tyrosine-phosphorylated HELZ2. The knockdown of SFPQ in 3T3-L1 cells downregulated mRNA levels of transcription factors including Krox20, Cebpß, and Cebpδ: key factors for early-stage adipocyte differentiation. In addition, knockdown of SFPQ inhibited 3T3-L1 cell differentiation to mature adipocytes. These findings demonstrated that SFPQ associating with HELZ2 is an important novel transcriptional regulator of adipocyte differentiation.

Administration of small-molecule guanabenz acetate attenuates fatty liver and hyperglycemia associated with obesity.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. However, there is currently no established treatment for NAFLD in obese human subjects. We previously isolated Helz2, the expression of which was upregulated in human and mouse NAFLD, and its deletion activated the hepatic expression of functional leptin receptor long form (Leprb) and suppressed NAFLD development and body weight (BW) gain in obese mice. A high-throughput assay of small-molecule drugs revealed that guanabenz acetate (Ga), originally used to treat hypertension, possesses a high affinity constant against HELZ2, and its administration activates LEPRB expression in HepG2 cells in vitro. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid ß-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice. This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. Regarding drug repositioning, Ga has the potential to effectively treat NAFLD and hyperglycemia in obese patients.

Transcriptional Regulation of the Angptl8 Gene by Hepatocyte Nuclear Factor-1 in the Murine Liver.

Brief refeeding times (~60 min) enhanced hepatic Angptl8 expression in fasted mice. We cloned the mouse Angptl8 promoter region to characterise this rapid refeeding-induced increase in hepatic Angptl8 expression. Deletion of the -309/-60 promoter region significantly attenuated basal promoter activity in hepatocytes. A computational motif search revealed a potential binding motif for hepatocyte nuclear factor 1α/1ß (HNF-1α/ß) at -84/-68 bp of the promoter. Mutation of the HNF-1 binding site significantly decreased the promoter activity in hepatocytes, and the promoter carrying the mutated HNF-1 site was not transactivated by co-transfection of HNF-1 in a non-hepatic cell line. Silencing Hnf-1 in hepatoma cells and mouse primary hepatocytes reduced Angptl8 protein levels. Electrophoretic mobility-shift assays confirmed direct binding of Hnf-1 to its Angptl8 promoter binding motif. Hnf-1α expression levels increased after short-term refeeding, paralleling the enhanced in vivo expression of the Angptl8 protein. Chromatin immunoprecipitation (ChIP) confirmed the recruitment of endogenous Hnf-1 to the Angptl8 promoter region. Insulin-treated primary hepatocytes showed increased expression of Angptl8 protein, but knockdown of Hnf-1 completely abolished this enhancement. HNF-1 appears to play essential roles in the rapid refeeding-induced increases in Angptl8 expression. HNF-1α may therefore represent a primary medical target for ANGPTL8-related metabolic abnormalities. The study revealed the transcriptional regulation of the mouse hepatic Angptl8 gene by HNF-1.

Genetics of Congenital Isolated TSH Deficiency: Mutation Screening of the Known Causative Genes and a Literature Review.

CONTEXT: Congenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified. OBJECTIVES: To define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations. PATIENTS AND METHODS: Thirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed. RESULTS: Genetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap. CONCLUSIONS: The mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.

Transducin ß-like 1, X-linked and nuclear receptor co-repressor cooperatively augment the ligand-independent stimulation of TRH and TSHß gene promoters by thyroid hormone receptors.

Mutations in TBL1X, a component of the nuclear receptor co-repressor (N-CoR) and silencing mediator of retinoic acid and thyroid hormone receptor co-repressor complexes, have recently been implicated in isolated central hypothyroidism (CeH). However, the mechanisms by which TBL1X mutations affect negative feedback regulation in the hypothalamus-pituitary-thyroid axis remain unclear. N-CoR was previously reported to paradoxically enhance the ligand-independent stimulation of TRH and TSHß gene promoters by thyroid hormone receptors (TR) in cell culture systems. We herein investigated whether TBL1X affects the unliganded TR-mediated stimulation of the promoter activities of genes negatively regulated by T3 in cooperation with N-CoR. In a hypothalamic neuronal cell line, the unliganded TR-mediated stimulation of the TRH gene promoter was significantly enhanced by co-transfected TBL1X, and the co-transfection of TBL1X with N-CoR further enhanced promoter activity. In contrast, the knockdown of endogenous Tbl1x using short interfering RNA significantly attenuated the N-CoR-mediated enhancement of promoter activity in the presence of unliganded TR. The co-transfection of N365Y or Y458C, TBL1X mutants identified in CeH patients, showed impaired co-activation with N-CoR for the ligand-independent stimulation of the TRH promoter by TR. In the absence of T3, similar or impaired enhancement of the TSHß gene promoter by the wild type or TBL1X mutants, respectively, was observed in the presence of co-transfected TR and N-CoR in CV-1 cells. These results suggest that TBL1X is needed for the full activation of TRH and TSHß gene promoters by unliganded TR. Mutations in TBL1X may cause CeH due to the impaired up-regulation of TRH and/or TSHß gene transcription despite low T3 levels.

Usage of continuous glucose monitoring (CGM) for detecting an unrecognized hypoglycemia and management of glucocorticoid replacement therapy in adult patients with central hypoadrenalism.

Patients with adrenal insufficiency require appropriate glucocorticoid replacement therapy; however, reliable biological parameters for optimizing glucocorticoid supplementation are limited. The physician has to rely primarily on clinical judgment, carefully taking into account signs and symptoms potentially suggestive of over- or under-replacement. We have found that some patients who are viewed as receiving sufficient doses of glucocorticoids occasionally exhibit morning headache or morning discomfort, which may be caused by unrecognized nocturnal hypoglycemia. Our aim in this study was to evaluate the usefulness of continuous glucose monitoring (CGM) for detecting unrecognized hypoglycemia and optimizing glucocorticoid replacement therapy in adult patients with central hypoadrenalism. Six patients with central hypoadrenalism of various etiologies were included in this study. All patients exhibited occasional morning headache or discomfort. We performed CGM to measure plasma glucose levels in all patients, and CGM identified unrecognized hypoglycemia episodes at midnight and early in the morning in five patients (83%). The CGM findings were used to fine-tune the dosing and regimens of glucocorticoid replacement and to re-evaluate glucose levels to avoid further unrecognized hypoglycemic events. This optimization of hydrocortisone supplementation prevented additional nocturnal hypoglycemia incidences in all cases. The addition of L-thyroxine with hydrocortisone continued to provide favorable glycemic control. Occasional symptoms also improved after maintenance in all patients. These findings demonstrated that CGM may represent a powerful tool for identifying unrecognized hypoglycemia and for optimizing supplementary hormones in patients with central hypoadrenalism, thereby improving their quality of life.

Pituitary NR4A1 is negatively regulated by thyroid hormone without direct binding of thyroid hormone receptors on the gene.

We previously reported that TRH stimulated pituitary TSHß gene expression via an immediate increase in NR4A1 in thyrotrophs. We demonstrated that NR4A1 mRNA levels are regulated by thyroid hormone. Pituitary NR4A1 mRNA levels were decreased in mice injected with L-T4. NR4A1 promoter activity was increased by the overexpression of TRßs, and these increases were decreased by T3, and the -27∼+152 bp region was responsible for these changes in vitro. An EMSA showed the lack of TRßs-isoforms binding, and a ChIP assay demonstrated the recruitment of TRßs and NCoR in the -147∼+148 bp region in the absence of T3, whereas T3 induced their release. Experiments on the overexpression and knockdown of NCoR, and using the mutant TRs supported the involvement of NCoR in the TR-induced stimulation. These results demonstrate that thyroid hormone down-regulated basal NR4A1 mRNA levels in the pituitary, and the direct binding of TR was not required.

Hypercalcemia after the Discontinuation of Medroxyprogesterone Acetate.

A 39-year-old woman was admitted to our hospital with symptoms of general fatigue, nausea, and vomiting that appeared three months after she stopped seven years of medroxyprogesterone acetate (MPA) medication for endometrial stromal sarcoma. Laboratory tests demonstrated moderate hypercalcemia. Several tests demonstrated that she was suffering from adrenal insufficiency. Glucocorticoid supplementation decreased her calcium level to a normal range, indicating that hypercalcemia was induced by adrenal insufficiency. It was suggested that she was suffering from MPA-induced adrenal insufficiency, but hypocortisolemia was being compensated by a high dose of MPA; hypocortisolemia and hypercalcemia then became evident after MPA treatment was discontinued.

Adrenal Ewing's Sarcoma in an Elderly Man.

Ewing's sarcoma usually arises in the bones of children and adolescents. We herein report a 74-year-old man with Ewing's sarcoma in the adrenal gland. The diagnosis was confirmed by a genetic test, pathological studies, and several imaging studies. He already had multiple liver metastases when he was transferred to our hospital and died on the 37th day. The diagnosis was further confirmed by autopsy studies. Adrenal Ewing's sarcoma is very rare, and our patient was older than other reported cases. Ewing's sarcoma should be considered even in elderly patients with adrenal tumors.

Continuous or Transient High Level of Glucose Exposure Differentially Increases Coronary Artery Endothelial Cell Proliferation and Human Colon Cancer Cell Proliferation.

We studied effect of high glucose levels on coronary artery endothelial cell proliferation and human colon cancer cell proliferation. To examine the long-term effect of glucose exposure on cell growth, cells were cultured for 14 days in the absence or presence of 183 mg/dL D-glucose addition in the culture medium. Short effect of elevated glucose levels was examined by addition of 183 mg/dL D-glucose addition in the culture medium for just one hour per day followed by changing the culture to standard medium (5.5 mM D-glucose) during the next 23-hours period. Cell proliferation was estimated by 2,3-Bis (2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carbox-anilide (XTT) assay and phosphor-Erk western blot analysis. We found that coronary artery endothelial cell proliferation was significantly increased in the culture medium with the acute one-hour addition of 183 mg/dL D-glucose compared to the absence or chronic presence of 183 mg/dL D-glucose addition in the culture medium. In contrast, colon cancer cell proliferation was significantly increased in the continuous presence of 183 mg/dL D-glucose addition in the culture medium compared to the acute one-hour addition of glucose. The extent of Erk2 phosphorylation paralleled with the relative changes in cellular proliferation in both cell types. Taken together, these results suggested that continuous or transient high level of glucose exposure differentially effects coronary artery endothelial and human colon cancer cell proliferation.

Fibroblast growth factor 21, assisted by elevated glucose, activates paraventricular nucleus NUCB2/Nesfatin-1 neurons to produce satiety under fed states.

Fibroblast growth factor 21 (FGF21), liver-derived hormone, exerts diverse metabolic effects, being considered for clinical application to treat obesity and diabetes. However, its anorexigenic effect is debatable and whether it involves the central mechanism remains unclarified. Moreover, the neuron mediating FGF21's anorexigenic effect and the systemic energy state supporting it are unclear. We explored the target neuron and fed/fasted state dependence of FGF21's anorexigenic action. Intracerebroventricular (ICV) injection of FGF21 markedly suppressed food intake in fed mice with elevated blood glucose. FGF21 induced c-Fos expression preferentially in hypothalamic paraventricular nucleus (PVN), and increased mRNA expression selectively for nucleobindin 2/nesfatin-1 (NUCB2/Nesf-1). FGF21 at elevated glucose increased [Ca2+]i in PVN NUCB2/Nesf-1 neurons. FGF21 failed to suppress food intake in PVN-preferential Sim1-Nucb2-KO mice. These findings reveal that FGF21, assisted by elevated glucose, activates PVN NUCB2/Nesf-1 neurons to suppress feeding under fed states, serving as the glycemia-monitoring messenger of liver-hypothalamic network for integrative regulation of energy and glucose metabolism.

HELZ2 Is an IFN Effector Mediating Suppression of Dengue Virus.

Flaviviral infections including dengue virus are an increasing clinical problem worldwide. Dengue infection triggers host production of the type 1 IFN, IFN alpha, one of the strongest and broadest acting antivirals known. However, dengue virus subverts host IFN signaling at early steps of IFN signal transduction. This subversion allows unbridled viral replication which subsequently triggers ongoing production of IFN which, again, is subverted. Identification of downstream IFN antiviral effectors will provide targets which could be activated to restore broad acting antiviral activity, stopping the signal to produce endogenous IFN at toxic levels. To this end, we performed a targeted functional genomic screen for IFN antiviral effector genes (IEGs), identifying 56 IEGs required for antiviral effects of IFN against fully infectious dengue virus. Dengue IEGs were enriched for genes encoding nuclear receptor interacting proteins, including HELZ2, MAP2K4, SLC27A2, HSP90AA1, and HSP90AB1. We focused on HELZ2 (Helicase With Zinc Finger 2), an IFN stimulated gene and IEG which encodes a promiscuous nuclear factor coactivator that exists in two isoforms. The two unique HELZ2 isoforms are both IFN responsive, contain ISRE elements, and gene products increase in the nucleus upon IFN stimulation. Chromatin immunoprecipitation-sequencing revealed that the HELZ2 complex interacts with triglyceride-regulator LMF1. Mass spectrometry revealed that HELZ2 knockdown cells are depleted of triglyceride subsets. We thus sought to determine whether HELZ2 interacts with a nuclear receptor known to regulate immune response and lipid metabolism, AHR, and identified HELZ2:AHR interactions via co-immunoprecipitation, found that AHR is a dengue IEG, and that an AHR ligand, FICZ, exhibits anti-dengue activity. Primary bone marrow derived macrophages from HELZ2 knockout mice, compared to wild type controls, exhibit enhanced dengue infectivity. Overall, these findings reveal that IFN antiviral response is mediated by HELZ2 transcriptional upregulation, enrichment of HELZ2 protein levels in the nucleus, and activation of a transcriptional program that appears to modulate intracellular lipid state. IEGs identified in this study may serve as both (1) potential targets for host directed antiviral design, downstream of the common flaviviral subversion point, as well as (2) possible biomarkers, whose variation, natural, or iatrogenic, could affect host response to viral infections.

Characteristics of Japanese aldosterone-producing adenomas with KCNJ5 mutations.

Somatic mutations in KCNJ5 gene have been identified in patients with adrenal aldosterone-producing adenomas (APAs). We previously reported that Japanese patients with APAs had distinct characteristics from patients in Western countries; i.e. they had a high frequency of KCNJ5 mutations and exhibited a frequent association with cortisol co-secretion. Therefore, APAs among Japanese patients may have different features from those in Western countries. We added recent cases, examined 47 cases (43% male) of APAs, including clinicopathological features, KCNJ5 mutations, and the mRNA levels of several steroidogenic enzymes, and compared the results obtained to those reported in other countries. While the prevalence of KCNJ5 mutations is approximately 40% in Western countries, 37 APA cases (78.7%) showed mutations: 26 with p.G151R and 11 with p.L168R. Although a significant gender difference has been reported in the frequency of KCNJ5 mutations in Europe, we did not find any gender difference. However, the phenotypes of Japanese patients with mutations were similar to those of patients in Western countries; patients were younger and had higher plasma aldosterone levels, lower potassium levels, and higher diastolic blood pressure. Reflecting these phenotypes, APAs with mutations had higher CYP11B2 mRNA levels. However, in contrast to APAs in Western countries, Japanese APAs with mutations showed lower CYP11B1, CYP17A1, and CYP11A1 mRNA levels. These findings demonstrated that Japanese APA patients may have distinct features including a higher prevalence of KCNJ5 mutations, no gender difference in the frequency of these mutations, and characteristics similar to the zona glomerulosa.

2016 Guidelines for the management of thyroid storm from The Japan Thyroid Association and Japan Endocrine Society (First edition).

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.

APPL1 promotes glucose uptake in response to mechanical stretch via the PKCζ-non-muscle myosin IIa pathway in C2C12 myotubes.

Expression of adaptor protein, phosphotyrosine interaction, pleckstrin homology domain, and leucine zipper containing 1 (APPL1) promoted glucose transporter 4 (GLUT4) translocation and glucose uptake in adipose and muscle tissues in response to stimulation with insulin, adiponectin, or exercise. In response to mechanical stretch, knockdown of APPL1 in C2C12 myotubes suppressed glucose uptake. APPL1-induced increased glucose uptake was mediated by protein kinase C (PKC) ζ but not AKT, AMPK, or calmodulin-dependent protein kinase. In myotubes overexpressing APPL1, PKCζ was phosphorylated and translocated to the plasma membrane (PM) in response to mechanical stretch. Phosphorylated PKCζ co-immunoprecipitated with protein phosphatase 2A (PP2A) under basal conditions, but dissociated upon myotube stretching. Moreover, stretch-induced phosphorylated PKCζ co-immunoprecipitated with non-muscle myosin IIa. Blebbistatin, an inhibitor of myosin II ATPase activity, suppressed APPL1-mediated stretch-induced glucose uptake and PKCζ translocation. Taken together these data demonstrate that in response to mechanical stretch, APPL1 enhances glucose uptake by modulating the activation and localization of PKCζ, as well as its functional interaction with both PP2A and myosin IIa. These findings support a new function for non-muscle myosin IIa in differentiated myotubes.

Nivolumab-induced hypophysitis in a patient with advanced malignant melanoma.

The anti-programmed cell death-1 monoclonal antibody (mab), nivolumab has recently been approved for the treatment of unresectable or metastatic malignant melanoma and non-small-cell lung cancers in Japan. Ipilimumab, an anti-cytotoxic T lymphocyte antigen-4 mab for malignant melanoma that was approved earlier than nivolumab in Western countries, is known to frequently cause endocrine immune-related adverse events such as hypophysitis and thyroid dysfunction. We herein report a patient with advanced melanoma who appeared to develop hypophysitis as a consequence of the inhibition of PD-1 by nivolumab. One week after the 6th administration of nivolumab, the patient developed progressive fatigue and appetite loss. Laboratory data on admission for the 7th administration of nivolumab showed eosinophilia and hyponatremia. Since ACTH and cortisol levels were low, nivolumab was discontinued and a large dose of hydrocortisone (100 mg/d) was promptly administered intravenously. A magnetic resonance imaging scan revealed the mild enlargement of the anterior pituitary gland and thickening of the stalk with homogenous contrast. A detailed assessment of anterior pituitary functions with hypothalamic hormone challenges showed that hormonal secretions other than ACTH and TSH were normal. With a replacement dose of hydrocortisone (20 mg/d), the 7th administration of nivolumab was completed without exacerbating the patient's general condition. The present report provides the first detailed endocrinological presentation of nivolumab-induced hypophysitis showing the enlargement of the pituitary gland and stalk in a malignant melanoma patient in Japan. Oncologists and endocrinologists need to be familiar with potentially life-threatening hypophysitis induced by immune-checkpoint inhibitors.

Reversible Hypopituitarism Associated with Intravascular Large B-Cell Lymphoma: Case Report of Successful Immunochemotherapy.

Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of diffuse large B-cell lymphoma. There have been only a limited number of reports regarding pituitary dysfunction associated with IVLBCL. We present a 71-year-old woman with hypopituitarism without any hypothalamic/pituitary abnormalities as assessed by magnetic resonance imaging. She presented with edema, abducens palsy, and elevated levels of lactate dehydrogenase and soluble interleukin-2 receptor. Provocative testing showed that the peaks of luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone and adrenocorticotropic hormone were evoked to normal levels by simultaneous administration of luteinizing hormone-releasing hormone, thyrotropin-releasing hormone and corticotropin-releasing hormone, but the responses of these four pituitary hormones showed a delayed pattern. She was diagnosed with IVLBCL with cerebrospinal invasion by pathological findings of the bone marrow, skin, and cerebrospinal fluid. She achieved hematological remission after immunochemotherapy. Pituitary function was also restored without hormonal replacement, and the improvement of the pituitary function was confirmed by dynamic testing. We reviewed the literature with respect to hypopituitarism associated with IVLBCL. There were less than 20 case reports and most of the patients died. Endocrinological course was described in only two cases, and both of them required hormonal supplementation. To our knowledge, this is the first case of hypopituitarism induced by IVLBCL that was successfully managed by immunochemotherapy alone. This case suggests that early diagnosis and treatment of IVLBCL might improve anterior pituitary function and enable patients to avoid hormone replacement therapy.

GNAS mutations in adrenal aldosterone-producing adenomas.

Mutations in GNAS, which encodes Gsα, have been documented in detail, particularly in human pituitary GH-secreting adenomas. Mutations have also recently been reported in adrenal cortisol-producing adenomas (CPAs), in addition to those in the PRKACA gene. However, mutations have not yet been examined in aldosterone-producing adenomas (APAs). Therefore, we herein investigated mutations in the GNAS gene in APAs. Two of the 15 (13%) CPAs with overt Cushing's syndrome and one of the 9 (11%) CPAs with subclinical Cushing's syndrome examined had the somatic mutations, p.R201S and p.R201C in the GNAS gene. We identified mutations in the GNAS gene (p.R201C) in 2 out of the 33 (6%) APAs tested, both of which showed autonomous cortisol secretion, while 24 APAs had mutations in the KCNJ5 gene (18 with p.G151R and 6 with p.L168R). These GNAS and KCNJ5 mutations were mutually exclusive in these adenomas. We herein demonstrated for the first time the presence of GNAS mutations in APAs, as well as in some cortisol-secreting adenomas. Our results suggest that these mutations, in addition to mutations in the KCNJ5 gene and other genes such as ATP1A1, ATP2B3 and CACNA1D, may be responsible for the tumorigenesis of APAs and CPAs with subclinical Cushing's syndrome.

Treatment and management of thyroid storm: analysis of the nationwide surveys: The taskforce committee of the Japan Thyroid Association and Japan Endocrine Society for the establishment of diagnostic criteria and nationwide surveys for thyroid storm.

OBJECTIVE: 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.