A Pregnant Woman with Excess Vasopressinase-Induced Diabetes Insipidus Complicated by Central Diabetes Insipidus like Lymphocytic Infundibulo-Neurohypophysitis.

Background: Gestational diabetes insipidus (DI) is a very rare complication of pregnancy. We present a case of gestational DI combining two different types of DI. Case Presentation. A 39-year-old pregnant woman suddenly presented with thirst, polydipsia, and polyuria after 31 gestation weeks (GWs). Based on laboratory findings of hypotonic urine (78 mOsm/kgH2O) with higher plasma osmolality (298 mOsm/kgH2O) and higher serum sodium levels (149 mEq/L), gestational DI was suspected, and the clinical course was monitored without therapy until the results of a measurement of plasma arginine vasopressin (AVP) levels were available. However, she subsequently developed acute prerenal failure and underwent an emergency cesarean section at 34 GWs. Her resected placenta weighed 920 g, nearly twice the normal weight. Immediately following delivery, intranasal 1-desamino-8-D-arginine vasopressin was administered, and her symptoms promptly disappeared. Afterward, her predelivery plasma AVP level was found to have been inappropriately low (0.7 pg/mL) given her serum sodium level. The patient's serum vasopressinase level just before delivery was 2,855 ng/mL, more than 1,000 times the upper limit of the normal range, suggesting excess vasopressinase-induced DI. The presence of anti-rabphilin-3A antibodies in the patient's blood, a hypertonic saline infusion test result, and loss of the high-intensity signal of the posterior pituitary on fat-suppressed T1-weighted magnetic resonance images without thickening of the stalk and enlargement of the neurohypophysis suggested concurrent central DI-like lymphocytic infundibulo-neurohypophysitis (LINH). Conclusion: In addition to the degradation of AVP by excess placental vasopressinase due to the enlarged placenta, an insufficient compensatory increase in AVP secretion from the posterior pituitary gland due to LINH-like pathogenesis might have led to DI symptoms.

HLA typing of patients who developed subacute thyroiditis and Graves' disease after SARS-CoV-2 vaccination: a case report.

BACKGROUND: Cases of subacute thyroiditis (SAT) after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination have been reported. A human leukocyte antigen (HLA) allele, HLA-B*35, appears to be involved in the pathogenesis of SAT. CASE PRESENTATION: We conducted HLA typing of one patient with SAT and another with both SAT and Graves' disease (GD), which developed after SARS-CoV-2 vaccination. Patient 1, a 58-year-old Japanese man, was inoculated with a SARS-CoV-2 vaccine (BNT162b2; Pfizer, New York, NY, USA). He developed fever (38 °C), cervical pain, palpitations, and fatigue on day 10 after vaccination. Blood chemistry tests revealed thyrotoxicosis and elevated serum C-reactive protein (CRP) and slightly increased serum antithyroid-stimulating antibody (TSAb) levels. Thyroid ultrasonography revealed the characteristic findings of SAT. Patient 2, a 36-year-old Japanese woman, was inoculated twice with a SARS-CoV-2 vaccine (mRNA-1273; Moderna, Cambridge, MA, USA). She developed fever (37.8 °C) and thyroid gland pain on day 3 after the second vaccination. Blood chemistry tests revealed thyrotoxicosis and elevated serum CRP, TSAb, and antithyroid-stimulating hormone receptor antibody levels. Fever and thyroid gland pain persisted. Thyroid ultrasonography revealed the characteristic findings of SAT (i.e., slight swelling and a focal hypoechoic area with decreased blood flow). Prednisolone treatment was effective for SAT. However, thyrotoxicosis causing palpitations relapsed thereafter, for which thyroid scintigraphy with 99mtechnetium pertechnetate was conducted, and the patient was diagnosed with GD. Thiamazole treatment was then initiated, which led to improvement in symptoms. CONCLUSION: HLA typing revealed that both patients had the HLA-B*35:01, -C*04:01, and -DPB1*05:01 alleles. Only patient 2 had the HLA-DRB1*11:01 and HLA-DQB1*03:01 alleles. The HLA-B*35:01 and HLA-C*04:01 alleles appeared to be involved in the pathogenesis of SAT after SARS-CoV-2 vaccination, and the HLA-DRB1*11:01 and HLA-DQB1*03:01 alleles were speculated to be involved in the postvaccination pathogenesis of GD.

Neurofibromatosis Type 1 with Concurrent Multiple Endocrine Disorders: Adenomatous Goiter, Primary Hyperparathyroidism, and Acromegaly.

We encountered a 70-year-old Japanese woman with neurofibromatosis type 1 (NF1) who had a history of pheochromocytoma and concurrently developed adenomatous goiter, primary hyperparathyroidism, and acromegaly. The patient had a somatotroph adenoma of the adenohypophysis that predisposed her to multinodular goiter. Three parathyroid tumors were detected by cervical ultrasonography and cervicothoracic computed tomography. Genetic analyses did not reveal genetic alterations (e.g. loss-of-function mutation) in the causative genes of endocrine tumors, including MEN1, RET, VHL, CDKN1B, and CDKN2C. The NF1 gene could not be analyzed genetically due to the patient's refusal. The pathophysiologic mechanisms of endocrinopathy concurrence in NF1 remain to be elucidated.

Differences in the birthweight of infants born to patients with early- or mid-to-late-detected gestational diabetes mellitus who underwent guideline-based glycemic control.

AIMS: To examine the effects of strict glycemic control on the birthweight of infants born to Japanese patients with early- or mid-to-late-detected gestational diabetes mellitus (ed- or md-GDM). METHODS: We retrospectively examined the characteristics of 101 patients with GDM who underwent guideline-based glycemic control. A 75-g oral glucose tolerance test was conducted to diagnose GDM at gestational weeks 11-15 (ed-GDM subgroup) and 24-28 (md-GDM subgroup). RESULTS: Infant birthweight was significantly lower in the ed-GDM subgroup (n = 25) than in the md-GDM subgroup (n = 76) (2688.3 ±â€¯470.4 g vs. 3052.4 ±â€¯383.1 g, p < 0.05), and the proportion of low-birthweight infants (<2500 g) was significantly higher in the ed-GDM subgroup than in the md-GDM subgroup (32.0% vs. 5.3%, p < 0.005). Fasting plasma glucose (FPG) levels during early treatment and before delivery were significantly lower in the ed-GDM subgroup than in the md-GDM subgroup (76.1 ±â€¯10.4 mg/dL vs. 85.5 ±â€¯9.6 mg/dL, p < 0.001; 80.5 ±â€¯10.4 mg/dL vs. 90.4 ±â€¯10.3 mg/dL, p < 0.0001). CONCLUSIONS: Patients with ed-GDM showed significantly lower FPG levels during treatment compared to those with md-GDM, presumably indicating an association with the delivery of low-birthweight infants.

Examination of Malignant Findings of Thyroid Nodules Using Thyroid Ultrasonography.

BACKGROUND: It is important to distinguish benign thyroid nodules from malignant thyroid nodules. Hence, this study aimed to determine the characteristics of patients with thyroid cancer using thyroid ultrasonography. METHODS: We retrospectively examined the ultrasonographic findings of 327 patients with 457 thyroid nodules (age: 59.9 ± 14.3 years; sex, n (%): female 242 (74.0%)) at a single center from 2014 to 2016. Ultrasonography was used to determine the nodule size, shape, border, internal echogenicity, presence of coarse calcifications and microcalcifications within the nodule, internal blood flow and whether the nodule was solid or contained cystic structures. Thyroid fine needle aspiration cytology (FNAC) was performed in all patients. The ultrasonographic findings were compared between patients with benign nodules and those with papillary thyroid carcinoma (PTC). Furthermore, in the analysis of anti-thyroglobulin (Tg) antibody-negative patients with single nodules, values of serum Tg/nodule volume were calculated and compared between patients with benign nodules and those with PTC. RESULTS: There were 298 (65.2%) benign nodules, 33 (7.2%) PTCs and 126 (27.6%) others (104 follicular neoplasms, 19 masses of undetermined significance and three other malignant tumors). The nodules diagnosed as PTC had significantly lower internal echogenicity (P < 0.01), more microcalcifications (P < 0.01) and comprised more nodules rich in blood flow (P < 0.05) than benign nodules. Solid nodules were found significantly more in the PTC group (P < 0.01). The serum Tg/nodule volume ratio was significantly higher in the PTC group (P < 0.05). CONCLUSIONS: Findings suggestive of PTC were found from images obtained using thyroid ultrasonography. In the diagnosis of PTC, the frequency of FNAC examinations should be reduced as this method is costly and invasive.

Clinical characterization of patients with primary aldosteronism plus subclinical Cushing's syndrome.

BACKGROUND: Primary aldosteronism (PA) plus subclinical Cushing's syndrome (SCS), PASCS, has occasionally been reported. We aimed to clinically characterize patients with PASCS who are poorly profiled. METHODS: A population-based, retrospective, single-center, observational study was conducted in 71 patients (age, 58.2 ± 11.2 years; 24 males and 47 females) who developed PA (n = 45), SCS (n = 12), or PASCS (n = 14). The main outcome measures were the proportion of patients with diabetes mellitus (DM), serum potassium concentration, and maximum tumor diameter (MTD) on the computed tomography (CT) scans. RESULTS: The proportion of DM patients was significantly greater in the PASCS group than in the PA group (50.0% vs. 13.9%, p <  0.05), without a significant difference between the PASCS and SCS groups. Serum potassium concentration was significantly lower in the PASCS group than in the SCS group (3.2 ± 0.8 mEq/L vs. 4.0 ± 0.5 mEq/L; p <  0.01), without a significant difference between the PASCS and PA groups. Among the 3 study groups of patients who had a unilateral adrenal tumor, MTD was significantly greater in the PASCS group than in the PA group (2.7 ± 0.1 cm vs. 1.4 ± 0.1 cm; p <  0.001), without a significant difference between the PASCS and SCS groups. CONCLUSIONS: Any reference criteria were not obtained that surely distinguish patients with PASCS from those with PA or SCS. However, clinicians should suspect the presence of concurrent SCS in patients with PA when detecting a relatively large adrenal tumor on the CT scans.

Weight control before and during pregnancy for patients with gestational diabetes mellitus.

AIMS/INTRODUCTION: The aim of the present study was to examine the associations of pregestational body mass index (BMI) and gestational weight change with birthweight for gestational age in Japanese mothers with gestational diabetes mellitus (GDM). MATERIALS AND METHODS: We retrospectively examined the clinical and laboratory characteristics of 101 mothers with GDM (pregestational BMI 24.7 ± 5.8 kg/m2 ; maternal age at delivery 34.7 ± 5.1 years; gestational age 38.5 ± 1.4 weeks) at a single center from January 2011 to December 2016. RESULTS: Gestational weight changes were 6.22 ± 5.39 kg, and infant birthweights were 2,987.3 ± 393.6 g. Multivariable analysis showed that, in all mothers, pregestational BMI and gestational weight change were positively associated with infant birthweight (P < 0.001 and P = 0.007, respectively). Pregestational BMI, but not gestational weight change, was positively associated with infant birthweight (P = 0.007) in 31 mothers with GDM who had pregestational BMI ≥25 kg/m2 ; in 68 mothers with GDM who had pregestational BMI 18.5-24.9 kg/m2 , only gestational weight gain was positively associated with infant birthweight (P = 0.039). Two mothers had pregestational BMI <18.5 kg/m2 . No statistically significant interactions of pregestational BMI with gestational weight change were found (P = 0.158). CONCLUSIONS: In mothers with GDM, pregestational BMI ≥25 kg/m2 and excessive gestational weight gain were significantly associated with increased infant birthweight. A prospective multicenter clinical study enrolling a larger number of mothers with GDM will be required to verify the effects of adequately controlling pregestational and gestational weights on infant birthweight for gestational age.

Administration of thiamazole for Graves' disease might trigger the onset of type 1 diabetes.

Thiamazole might trigger the onset of type 1 diabetes.

Comparison of efficacy and adverse effects between methimazole 15 mg+inorganic iodine 38 mg/day and methimazole 30 mg/day as initial therapy for Graves' disease patients with moderate to severe hyperthyroidism.

BACKGROUND: Methimazole (MMI) is usually used at an initial dose of 30 mg/day for severe Graves' disease (GD) hyperthyroidism, but adverse effects are more frequent at this dose than at MMI 15 mg/day. OBJECTIVES: We designed a regimen to address the lack of a primary therapeutic effect of the MMI 15 mg/day by combining it with inorganic iodine at 38.2 mg/day. Our aim was to compare the two regimens (MMI 15 mg+inorganic iodine at 38.2 mg/day (M15+I) vs. MMI 30 mg/day (M30)) in terms of therapeutic effect, adverse effects, and remission rate. DESIGN AND PATIENTS: In a prospective study, 310 patients with untreated GD (serum free thyroxine (fT4) ≥5 ng/dL) were assigned to one of the two regimens. Potassium iodide was discontinued in the M15+I group as soon as the serum fT4 level was within the reference range (0.8-1.6 ng/dL). RESULTS: Percentages of patients achieving an fT4 level within reference range in ≤30, ≤60, or 90 days on the study treatment regimens were 45.3%, 73.9%, and 82.0% respectively for the M15+I group, and 24.8%, 63.1%, and 75.2% respectively for the M30 group. Hence, the proportions of patients achieving this goal in ≤30 or ≤60 days were significantly larger in the M15+I group. Adverse effects that required discontinuation of MMI were more frequent in the M30-treated than in the M15+I-treated group (14.8% vs. 7.5%; p=0.0387). The remission rates in the M15+I and M30 groups were 19.9% and 14.8%-higher in the former, but the difference did not reach statistical significance. CONCLUSION: The results of this study raise the possibility that M15+I is superior to M30 as a primary treatment for moderate to severe hyperthyroidism caused by GD.

Tumor-induced osteomalacia: benign tumor recurrence after two surgical resections at two different medical institutions.

OBJECTIVE: To describe an exceedingly rare case of tumor-induced osteomalacia (TIO) caused by a benign phosphaturic mesenchymal tumor that recurred after two surgical resections at two different medical institutions. METHODS: A 69-year-old man complained of a 3-year history of persistent whole body pain and presented with hypophosphatemia, elevated serum levels of bone-specific alkaline phosphatase and fibroblast growth factor-23 (FGF-23), and multiple fractures. The patient was suspected of having TIO. We conducted the following diagnostic modalities considered useful to detect the tumor: serum FGF-23 level measurement in the extremities, positron emission tomography (PET)-computed tomography (CT),and magnetic resonance imaging (MRI). RESULTS: The causative tumor could be detected in the right humerus not by venous catheterization for serum FGF-23 level measurement but by the combination of PET-CT and MRI. The authors, who had successfully treated two patients with TIO, visually confirmed the absence of any tumor residue during tumorectomy. Nevertheless, the tumor recurred after surgery. The residual tumor could be localized in the right humerus not by PET-CT but by the combination of superficial venous sampling at 10 sites and MRI. The residual tumor recurred after the second tumorectomy at another hospital. This patient indicates that the possibility--a benign causative tumor may not be completely resected by surgery--cannot be ruled out thoroughly. CONCLUSION: Superficial venous sampling at multiple sites may be a surrogate for venous catheterization. Patients with TIO should be meticulously followed-up after surgery to detect any residual tumor by periodic biochemical monitoring and by imaging modalities accordingly.

Prevalence of malignant tumors and adenomatous lesions detected by ultrasonographic screening in patients with autoimmune thyroid diseases.

BACKGROUND: Thyroid ultrasonography (US) is the most sensitive method for detecting thyroid nodules, and US-guided aspiration biopsy is the most accurate diagnostic procedure for thyroid nodules. We performed this retrospective study to establish the prevalence of thyroid nodules in Graves' disease and patients with Hashimoto's thyroiditis at the time of their initial visit. METHODS: We performed thyroid US as routine screening in 1652 patients with Graves' disease and 2036 Hashimoto's thyroiditis and performed US-guided fine-needle aspiration biopsy when the diameter of a nodule >1 cm or a nodule was suspected of being malignant. RESULTS: The prevalence of papillary carcinoma in the patients with Hashimoto's thyroiditis was higher than in the patients with Graves' disease (1.77% vs. 0.97%), and two patients with Hashimoto's thyroiditis (0.098%) were found to have malignant lymphoma. Adenomatous lesions were observed more frequently in the patients with Hashimoto's thyroiditis than in the patients with Graves' disease. The prevalence of adenomatous lesions increased in an age-dependent manner in both the patients with Graves' disease and those with Hashimoto disease; and adenomatous lesions were more frequent in younger patients with Hashimoto' s thyroiditis than in those with Graves' disease. CONCLUSIONS: The prevalence of both thyroid papillary cancer and adenomatous lesions was greater in the patients with Hashimoto's thyroiditis than in those with Graves' disease; and adenomatous lesions were more frequent in younger patients with Hashimoto's thyroiditis. We recommend performing US at the time of the initial visit in patients with autoimmune thyroid disease, who have a high prevalence of thyroid papillary carcinoma, to detect malignant thyroid tumors and adenomatous lesions.

[Diabetic osteopahty and vitamin K].

Diabetes mellitus is considered as a risk factor for fractures, and there are some reports showing that metabolic effects of poor glycemic control resulted in lower bone turnover. Previous studies have revealed that this reduction of bone turnover increases bone fragility, independently of bone mineral density, so that the mechanisms of diabetic osteopahty seem to be more closely related to bone quality than bone quantity. The mechanisms of the preventive effect on fractures by vitamin K treatment should be related to amelioration of bone quality via increasing amounts of carboxylated osteocalcin. Therefore, administration of vitamin K(2) (menatetrenone) to the patients with diabetic osteopathy will be beneficial in order to improve the impaired bone quality and to reduce fracture risk.

Stability of A+U-rich element binding factor 1 (AUF1)-binding messenger ribonucleic acid correlates with the subcellular relocalization of AUF1 in the rat uterus upon estrogen treatment.

The nucleocytoplasmic shuttling protein, A+U-rich element binding factor 1 (AUF1), is one of the RNA-binding proteins that specifically bind adenylate-uridylate rich elements (AREs) in mRNA 3'-untranslated regions (UTRs), and acts as a regulator of ARE-mediated mRNA degradation in the cytoplasm. We previously reported that in the female rat uterus, the levels of specific AUF1 isoform mRNAs (p40/p45) were increased by 17 beta-estradiol (E2) treatment. Therefore, we examined the role of AUF1 in the regulation of E2-mediated mRNA turnover in the rat uterus. We identified ABIN2 and Ier2/pip92 mRNAs as candidate targets of AUF1 in the rat uterus. We found that AUF1-binding elements were present in the 3'-UTR of both mRNAs and that the 3'-UTRs functioned as mRNA turnover regulatory elements. In the ovariectomized rat uterus, the nucleocytoplasmic localization of AUF1p40/p37 isoform proteins was regulated by E2. We also found that cytoplasmic AUF1-bound mRNA levels changed coincidentally with the cytoplasmic levels of AUF1p40/p37. Finally, we confirmed that the subcellular localization of AUF1p40 controlled the stability of target mRNAs in vitro, such that cytoplasmically localized AUF1p40 led to marked mRNA stabilization, whereas nuclear-localized AUF1p40 stabilized target mRNA only slightly. These results suggested that E2-inducible ARE-containing gene transcripts are regulated, at least in part, via mRNA stabilization through the nucleocytoplasmic relocalization of AUF1.

Interaction between 3' untranslated region of calcitonin receptor messenger ribonucleic acid (RNA) and adenylate/uridylate (AU)-rich element binding proteins (AU-rich RNA-binding factor 1 and Hu antigen R).

Our previous results in mouse osteoclasts suggested that calcitonin (CT) alters CT receptor (CTR) mRNA stability. The CTR mRNA transcript contains several adenylate/uridylate (AU)-rich destabilizing elements in the 3' untranslated region (3'UTR). When the 3'UTR of mouse CTR mRNA was labeled by [alpha-(32)P]-uridine 5-triphosphate, interactions were observed between the transcript and several cell extracts, including those from the osteoclast progenitor monocyte/macrophage cell line, RAW 264.7. The molecular masses of the interacting proteins ranged from approximately 35 to 50 kDa, similar to AU-rich RNA-binding factor 1 (AUF1) and Hu antigen R (HuR). Radiolabeled 3'UTR transcripts bound with a 40-kDa protein, which could be extracted from cells transfected with AUF1 p40. To confirm the binding specificity, a pSG5 vector construct, containing the AUF1 p40 with an hemagglutinin tag, was transiently transfected into NIH3T3 cells. The extracts were incubated with poly(A)-added CTR3'UTR. The reaction mixture was immunoprecipitated using an antihemagglutinin antibody and precipitated mRNA species were extracted and reverse transcribed using oligo-dT primers. It was found that PCR primers specific for the 3'UTR of CTR mRNA sequence generated a PCR signal. No signal was observed when mutated AUF1 p40 was transfected. In a manner similar to the AUF1 binding, HuR was also found to bind to the 3'UTR. Specific binding of AUF1 p40 and HuR was also found with RNA extracted from mouse osteoclasts. Treatment of osteoclasts with CT did not significantly affect the expression of AUF1 but decreased the levels of HuR and its mRNA. The role of CTR3'UTR in mRNA stability was further tested by expressing luciferase reporter constructs that did, or did not, contain the CTR3'UTR, under the control of the tetracycline-regulatory system. The results showed that the addition of 3'UTR considerably shortened the mRNA half-life of the luciferase reporter gene. These results suggest that AUF1 p40, HuR, and the 3'UTR of the CTR mRNA transcript could be involved in posttranscriptional regulation of CTR mRNA expression.

[Glucocorticoid-induced osteoporosis].

Glucocorticoid-induced osteoporosis is one of the major complications of long-term exposure to supraphysiological doses of glucocorticoid. It has been recognized that bone loss is rapid, particularly in the first 6 months of the therapy. The skeletal effects are both dose and duration dependent; daily glucocorticoid therapy at doses of 7.5 mg/day of prednisolone or above leads to decrease bone mass and increase risk of fractures. The mechanisms which glucocorticoid induces osteoporosis are suppression of bone formation and increase of bone resorption. Hypogonadism also contributes to this pathological condition via direct suppression of sex steroids and indirect suppression through decreased secretion of pituitary hormones. Estrogen, vitamin D and its active analogues, and calcitonin, have been therefore used to prevent glucocorticoid-induced osteoporosis; however, the effectiveness is somehow limited. Treatment with newly developed anti-resorptive amino-containing bisphosphonates such as alendronate and risedronate, showed significant increase of bone mineral density for both the prevention and the treatment of glucocorticoid-induced osteoporosis, as well as risk reduction of fractures in the patients. These bisphosphonates provide a better consequence for the treatment of glucocorticoid-induced osteoporosis.

A case of primary mucoepidermoid carcinoma of the thyroid: molecular evidence of its origin.

Primary mucoepidermoid carcinoma (MEC) of the thyroid is very rare, and its origin has not been fully determined. We report a case of MEC, the origin of which was demonstrated by thyroid specific genes expressed in a metastatic lymph node. A 52-year-old male presented with chest pain, weight loss and diffuse goitre. Ultrasonography showed the thyroid to be diffusely enlarged with numerous small calcifications. The tumour was found to be infiltrating the thyroid, lung, lymph nodes and first thoracic vertebra. A variant type of papillary thyroid carcinoma was suspected by fine needle aspiration cytology of the thyroid. An open biopsy specimen from an axillary lymph node revealed the tumour to be composed of three distinct cell types: mucin-producing cells, intermediate cells and a small amount of epidermoid cells with scattered psammoma bodies. Immunohistochemical studies showed the tumour cells to be negative for thyroglobulin and calcitonin, but positive for CEA. To examine the primary origin of the tumour, the expression of thyroid specific genes in the lymph node specimen was examined by RT-PCR. TTF-1, TTF-2, Pax-8, Na-I symporter and thyroid peroxidase mRNA were detected. The presence of these thyroid-specific mRNAs indicates that this MEC originated from thyroid follicular epithelium. This is the first molecular evidence of dedifferentiation from thyroid follicular cells to MEC.