This phase 1 dose-escalation study evaluated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of K1-70^TM, a TSH-receptor-specific monoclonal autoantibody that inhibits ligand binding and receptor activation, in Japanese Graves’ disease (GD) patients. Twelve patients were enrolled, divided into four dosage cohorts (5 mg, 25 mg, 75 mg, and 150 mg), and monitored for 100 days post-administration. The primary objective was to assess safety and tolerability, and the secondary objectives were evaluation of PK and thyroid function. Exploratory analyses focused on the dynamics of the anti-TSH receptor antibodies and Thyroid eye disease (TED). K1-70^TM demonstrated a favorable safety profile, with no reports of serious adverse events. Mild to moderate treatment-emergent adverse events, such as headache and fatigue, were observed in 83.3% of the participants, but none were deemed severe. PK analysis revealed a dose-dependent increase in half-life, suggesting prolonged systemic exposure at higher doses. Thyroid function remained stable at lower doses, but there were dose-dependent reductions at higher doses that were managed with adjunctive L-thyroxine therapy. Marked reductions in TSAb levels were observed across all cohorts, indicating effective suppression of TSH receptor activity. An improvement in proptosis was noted in 50% of the eyes, suggesting a potential therapeutic benefit against inactive-phase TED. These findings support K1-70^TM as a promising targeted therapy for GD and TED, and they warrant further studies involving larger patient populations and active disease phases to confirm its efficacy and safety (jRCT Registration Number: JRCT2080224902).

To elucidate the clinicopathological features of follicular thyroid carcinoma (FTC) coexisting with papillary thyroid carcinoma (PTC) (FTC + PTC). We collected a total of 55 FTC + PTC patients (including 12 males [21.8%] and 43 females [78.2%]), with an average age of 47.6 years. In the FTC alone group, the average age was 52.3 years, and the proportion of females was 71.3%. The median age was 43.5 years, with an average age of 45 years in the PTC alone group. Compared with the tumors in the FTC alone group, FTC in the FTC + PTC group exhibited a smaller maximum diameter (49.1% measuring ≤2 cm), a younger patient age (70.9% younger than 55 years), an earlier tumor stage (94.5% in stages I–II), a lower incidence of recurrent cancer (n = 2, 3.6%), a lower frequency of distant metastasis (6.1%), and a lower proportion of “extensively invasive” subtype (12.7%) (all p < 0.05). Compared with the PTC alone group (n = 289), the FTC + PTC group had a higher proportion of PTC with a maximum diameter of ≤1 cm (72.5%), and the degree of invasion of thyroid extracellular tissue was less severe (all p < 0.05). No statistically significant differences were found in overall survival (OS), cancer-specific survival (CSS), and RFS between these two groups (the FTC or PTC alone group versus FTC + PTC group). In sum, FTC + PTC has some clinicopathological features.

Chronic kidney disease (CKD) induces secondary osteoporosis, characterized by an imbalance between bone formation and resorption due to kidney dysfunction; the result is a reduction in both bone mineral density and quality. This condition is compounded by disruption of bone metabolic turnover, abnormalities in bone microstructure and collagen cross-linking, and compromised bone quality, all of which contribute to increased bone fragility. Reduced kidney function is complicated by secondary hyperparathyroidism, which exacerbates bone fragility. Managing osteoporosis in patients with CKD is challenging because drugs may be contraindicated or require cautious administration, particularly those with high urinary excretion rates. In addition, severe hypercalcemia or hypocalcemia may develop in these patients following administration of active vitamin D or denosumab, respectively. The choice of pharmacotherapy depends on the stage of CKD; however, evidence for the safety and efficacy of osteoporosis drugs in moderate to severe cases of CKD, particularly stages G4, G5, and G5D (i.e., dialysis patients), is limited. This article focuses on the pathophysiology of CKD-associated osteoporosis, as well as the increased fracture risk, and provides a concise overview of safety considerations regarding administration of osteoporosis drugs in Japan. The data presented highlight the complexities associated with drug use in patients with CKD.

The parathyroid glands (PTGs) regulate calcium metabolism by secreting parathyroid hormone (PTH). Patients with hypoparathyroidism require lifelong replacement therapy, which is associated with risks of chronic kidney disease, bone fractures, and a reduced quality of life. Generating PTGs from pluripotent stem cells (PSCs) offers a potential regenerative therapy for this condition. This review first explains PTG organogenesis, followed by an overview of both in vitro and in vivo approaches to PTG generation. In vitro studies have successfully induced PTH-expressing parathyroid cells from human PSCs. However, challenges remain, particularly in achieving sufficient PTH secretion and functional efficacy in vivo. Meanwhile, an in vivo organ generation technique known as blastocyst complementation has successfully produced functional PTGs in rodents. However, whether this technology can be applied using human PSCs and animal embryos remains unclear. Pluripotent stem cell-derived PTGs hold promise for both clinical applications and basic research, but further advancements will be necessary to overcome existing challenges in this field.

The prevalence of metabolic syndrome (MS) is rising due to lifestyle changes. To investigate the pathogenesis of MS and identify potential biomarkers, bioinformatics tools were used to screen for MS-related genes, such as Fras-1-related extracellular matrix protein 2 (FREM2), and miRNAs, including miR-28-5p and miR-424-5p. An insulin resistance (IR) cell model was established by treating human liver cells with insulin. The roles of FREM2, miR-28-5p, and miR-424-5p in IR were examined through overexpression and silencing experiments. Transfection of miR-28-5p/miR-424-5p mimics and a dual-luciferase assay were performed to explore their regulation of FREM2. The diagnostic value of miR-28-5p/miR-424-5p in MS was assessed using the receiver operating characteristic (ROC) curve. Increased expression of FREM2 and suppression of miR-28-5p/miR-424-5p enhanced glucose uptake in IR cells. Transfection with miR-28-5p or miR-424-5p mimics reduced luciferase activity in cells transfected with the wild-type FREM2 reporter vector and suppressed FREM2 expression. The ROC curve analysis indicated that miR-28-5p and miR-424-5p serve as effective classifiers for MS, with their combined use offering higher reliability. In conclusion, miR-28-5p and miR-424-5p exacerbated IR progression in human liver cells (HHL-5) through the negative regulation of FREM2, and they are potential biomarkers for MS.

Bilirubin is associated with vascular complications in diabetes. However, the correlation between bilirubin and sarcopenia or muscle strength has not been investigated. This study aimed to investigate the association between total bilirubin and skeletal muscle mass index (SMI), hand grip strength (HGS), and sarcopenia in patients with type 2 diabetes. This cross-sectional study included 1,108 patients with type 2 diabetes from three hospitals in Japan. Multiple and logistic regression analyses were used to examine the relationships between total bilirubin and SMI, HGS, and sarcopenia. Of the participants, 473 (43%) were women. The median (interquartile range) age, and glycated hemoglobin were 67 (59–73) years, and 7.4 (6.7–8.6) %, respectively. The median SMIs for women and men were 6.32 (5.73–7.04) kg/m² and 7.53 (7.02–8.19) kg/m², respectively. The median HGS for women and men were 21.5 (17.5–25.0) kg and 36.0 (30.0–41.5) kg, respectively. Sarcopenia was present in 11% and 12% of women and men, respectively. No correlation was observed between total bilirubin and SMI in both sexes. No significant association was observed between total bilirubin and HGS in men, whereas a positive correlation was observed in women (β = 0.18, p = 0.01). Total bilirubin was negatively associated with sarcopenia in women (odds ratio = 0.80, 95% confidence interval: 0.64–0.98, interaction p = 0.02). The total bilirubin was significantly associated with HGS and sarcopenia in women with type 2 diabetes. Total bilirubin may serve as a useful indicator of sarcopenia in Japanese women.

Childhood obesity is a growing global health concern, contributing to numerous non-communicable diseases and long-term health complications. The prevalence of obesity in children and adolescents continues to rise, driven by complex interactions among various factors. The key risk factors include both environmental and genetic influences. Environmental factors include family elements like household conditions and lifestyle, while genetic factors refer to inherited predispositions. More recently, epigenetic factors have gained attention, focusing on chemical modifications such as DNA methylation that are influenced by the prenatal and early-life environment and may contribute to obesity risk. Unlike obesity in adults, the risk factors for obesity in children are largely dependent on their family environments rather than individual behaviors. For effective intervention, it is important to identify at-risk children and their families as early as possible after birth. Despite advances in machine learning, polygenic risk scores, and epigenomic markers—which show promise as being more accurate and comprehensive prediction methods—no risk prediction models are currently in clinical use. Achieving predictions with higher accuracy, external validation, and consideration of population-specific factors (e.g., ethnic variability) while avoiding bias or stigma in targeted interventions is needed for effective childhood obesity prevention. Herein, we summarize environmental, genetic, and epigenetic risk factors for childhood obesity and review the unique situations and regional factors in Japan, which are the focus of our study. Furthermore, we introduce the major advances in risk prediction models for childhood obesity.

Children with idiopathic short stature (ISS) and growth hormone deficiency (GHD) exhibit imbalances in gut microbiota (GM), and the latter is related to endocrine hormones (such as insulin-like growth factor 1 (IGF-1)). The current study investigated the compositional and functional variations in GM between children with ISS and GHD, employing 16S rRNA sequencing technology. Sequencing results from 15 children with ISS and 18 children with GHD indicated no significant differences in GM alpha diversity or phylum-level diversity between the ISS and GHD groups. At the genus level, the abundance of Terrisporobacter was significantly greater in the ISS group compared to the GHD group, whereas the abundance of Acidovorax was reduced. The abundance of Prevotella stercorea and uncultured Sutterella sp. at the species level was significantly lower in the ISS group compared to the GHD group. The third level (L3) of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database revealed functional variations in GM, with children in the ISS group having higher levels of intestinal bacteria Mobility Proteins and Background Chemotaxis. Despite these differences, the overall composition and function of GM between ISS and GHD children were not significantly different, indicating that the mechanisms by which GM influences the growth and development of children in both groups may be similar. This study was registered with the Medical Research Registration and Record System with the registration number MR-44-24-045472.

Glucose-dependent insulinotropic polypeptide (GIP) is secreted by enteroendocrine K cells, primarily located in the upper small intestine, in response to food intake and plays a significant role in the postprandial regulation of nutrient metabolism. Although the importance of GIP in metabolic regulation has long been recognized, progress in developing GIP as a therapeutic target has been limited. However, the GIP/GIP receptor (GIPR) axis has garnered increasing attention in recent years. Emerging evidence suggests that dual GIP/GLP-1 receptor agonists and triple GIP/GLP-1/glucagon receptor agonists provide beneficial metabolic effects in individuals with type 2 diabetes and obesity. In this review, we outline the physiological roles of GIP, detailing the mechanisms of GIP secretion from K cells in response to macronutrients, its actions on key target organs involved in metabolic regulation, and ongoing developments in its therapeutic applications.

Multiple endocrine neoplasia type 2B (MEN2B) is a rare autosomal dominant disorder caused by germline pathogenic RET variants. On the other hand, Charcot–Marie–Tooth disease (CMT) is a hereditary neurological disorder, characterized by distal muscle weakness and sensory loss, with approximately 100 identified causative genes. Herein, we report a de novo RET mutation in a patient presenting with clinical features of both MEN2B and CMT. The patient, a 22-year-old woman, had a history of lower limb muscle weakness, with no family history of MEN2B or CMT. The patient was being treated for a thyroid gland neoplasm. Genetic testing of the medullary thyroid carcinoma revealed a previously unreported RET germline variant, p.M918W (RET: c.2752_2753delinsTG, p.Met918Trp). The novel p.M918W RET variant was associated with concurrent MEN2B and CMT. This finding was unexpected as MEN2B typically manifests with distinct features, such as marfanoid habitus and mucosal neuromas, but not with muscle weakness, as seen in CMT. Based on this finding, the plausible role of the p.M918W mutation as a shared pathway for both MEN2B and CMT warrants further investigation.

No evidence-based standards exist regarding levothyroxine (LT4) replacement therapy initiation timing in patients with hyperthyroid Graves’ disease undergoing total thyroidectomy. Although LT4 replacement from the first postoperative day has been the standard of care at our hospital, its clinical validity has not been thoroughly examined. This study investigated the perioperative kinetics of thyroid hormones to assess the safety and efficacy of early LT4 initiation. Thirty patients with Graves’ disease (18 hyperthyroid and 12 euthyroid) and 12 with thyroid nodules who underwent total thyroidectomy were included. Blood samples were collected from each patient for thyroid hormone measurement on the day before surgery (D-1), 15 min after surgery (D0), at 8:00 am on days 1 (D1) and 3 (D3), and 3 weeks (W3) and 3 months (M3) after surgery. In 18 patients with hyperthyroid Graves’ disease, serum free triiodothyronine (FT3) levels significantly decreased immediately after surgery and were within the normal range by D1. Although LT4 was started on D1, FT3 levels continued to decline by D3 and remained low at W3 and M3. Serum FT4 levels followed a slower decline but remained within the normal range for M3. In patients with euthyroid Graves’ disease and those with thyroid nodules, hormone levels stayed within or around the reference range throughout the observation period. In conclusion, initiating LT4 on the day after surgery is safe and effective for maintaining thyroid function in patients with hyperthyroid Graves’ disease undergoing total thyroidectomy. These results could inform future guidelines, supporting earlier postoperative LT4 initiation.

Hypopituitarism, characterized by reduced secretion of pituitary hormones, profoundly impacts systemic metabolic homeostasis and quality of life. Its etiology ranges from congenital anomalies in pituitary development to acquired conditions involving inflammation and autoimmune processes. Despite advances in understanding its pathogenesis, diagnostic challenges persist, particularly in cases with complex extra-pituitary manifestations or novel genetic variations. Congenital hypopituitarism often stems from disruptions in transcription factors and signaling pathways critical for pituitary organogenesis. Emerging studies employing next-generation sequencing and developmental biology techniques have revealed new genetic loci and mechanisms implicated in combined pituitary hormone deficiency. However, the pathogenesis of most congenital cases remains elusive, underscoring the need for functional and phenotypic analyses of novel variants. Acquired hypopituitarism, frequently associated with pituitary tumors or systemic diseases, has also been increasingly linked to autoimmune mechanisms. Notably, the concept of paraneoplastic autoimmune hypophysitis has emerged, highlighting malignancy-driven immune responses as a novel etiological framework. Investigations into immune checkpoint inhibitor-related hypophysitis and anti-PIT-1 hypophysitis exemplify the intricate interplay between tumor immunity and endocrine dysfunction, suggesting shared mechanisms involving ectopic antigen expression and autoimmunity. This review synthesizes recent insights into the genetic, developmental, and immunological underpinnings of hypopituitarism. By exploring both congenital and acquired etiologies, we aim to bridge gaps in the current understanding of this complex disorder and provide a foundation for improved diagnostic and therapeutic strategies. Future perspectives emphasize the integration of advanced genetic tools, deeper exploration of tumor-immunity interactions, and a heightened focus on extra-pituitary phenotypes to refine clinical practice and enhance patient outcomes.

Thyroid storm (TS) is a rare but fatal endocrine emergency with high mortality, and there have been few detailed reports on its severity and possible complications to date. Therefore, a single-center retrospective survey was conducted to comprehensively analyze the severity, treatments, and complications of patients with thyroid storm who were admitted to Kitasato University Hospital between 2012 and 2023. A total of 22 patients who experienced thyroid storm were extracted; 19 patients (86%) had Graves’ disease, among which 12 patients were newly diagnosed, and there were 4 fatalities (18.1%) during the study period. The median Acute Physiology and Chronic Health Evaluation II (APACHE II) score and median Sequential Organ Failure Assessment (SOFA) score were 20 and 5, respectively, and both scores were higher in critical patients who needed ventilation, continuous hemodialysis and filtration, therapeutic plasma exchange, percutaneous cardiopulmonary support, extracorporeal membrane oxygenation, or who finally died. Diagnostic criteria for disseminated intravascular coagulation (DIC) were met in five patients (23%) who had significantly higher scores on the Burch-Wartofsky Point Scale as well as APACHE II and SOFA scores than the other patients. Thus, DIC is a frequent and critical complication of TS, which can lead to severe consequences, suggesting the necessity of prompt and intensive management of these patients.

Some cases of obesity are thought to be associated with hypo-leptinemia. This may cause decreased appetite suppression resulting in increased appetite, leading to weight gain. Replacement therapy with leptin might be theoretically useful, but verification by reporting more cases is required. Here, we first investigated the serum leptin levels and their correlation with body mass index (BMI) in 107 patients with obesity to identify the subjects with hypo-leptinemia. Among them, one patient with congenital hypopituitarism was further investigated by comparison of his clinical and pathological characteristics with those of control subjects. This 40-year-old Japanese man, who was large from birth, consistently showed obesity of more than 2SD during his growth period. He had 41.5 kg/m² at BMI with central hypogonadism, central diabetes insipidus and severe growth hormone deficiency, cognitive impairment, and abnormal eating behavior, which led to suspicion of the involvement of hypothalamic factors. Genetic analysis revealed no definite mutations regarding metabolic and nutritional systems or adipocytes including leptin-related genes. Electron microscopic images of subcutaneous adipose tissue demonstrated relatively smaller adipocytes compared with a BMI-matched patient. The patient suffered from his abnormal eating behavior, began dialysis at the age of 41 years, and died of bacterial pneumonia at 49 years of age. Among patients with severe obesity with hypo-leptinemia, there could be patients with disturbance of healthy expansion in adipocyte, probably due to unknown dysfunction. Even with the lack of abnormality of leptin-related genes, indication of leptin-replacement may be considered for severely obese patients with hypo-leptinemia.

The association between hypertensive disorders of pregnancy (HDP) and the subsequent development of type 2 diabetes (T2D) in Japanese general population remains unclear. To investigate the influence of HDP on long-term postpartum development of metabolic disorders and T2D, we conducted a population-based cross-sectional study using the 75 g oral glucose tolerance test (75g-OGTT) in 978 parous Japanese women (median age: 66 years). We further evaluated the combined effect of HDP and T2D susceptibility genes on developing T2D. HDP history was identified in 101 participants (10.3%) and associated with high blood pressure, hypertriglyceridemia, increased homeostasis model assessment 2 for insulin resistance, decreased Matsuda index and insulin secretion-sensitivity index-2, increased postprandial glucose levels during the 75g-OGTT, and increased prevalence of hypertension, metabolic syndrome and T2D. The age and BMI adjusted odds ratio (OR) for T2D was 1.74 (95%CI: 1.04–2.93) in individuals with HDP as compared to those without HDP. Stratified analyses demonstrated an increased OR of T2D prevalence for individuals with HDP history harboring the cyclin-dependent kinase 5 regulatory subunit associated protein 1-like 1 (CDKAL1) C/C genotype compared with that of the reference group after adjusting for age and current BMI (OR = 5.18 vs. reference group; 95% CI: 1.99–13.50). Further, validation analyses using bootstrap method showed high reproducibility. HDP history was associated with postpartum prevalence of hypertension, insulin resistance and T2D later in life in Japanese general population. Further, the simultaneous assessment of an HDP history and CDKAL1 genotype is valuable to predict the future T2D development (UMIN000036074).

The 2017 World Health Organization classification described aggressive pituitary neuroendocrine tumor (PitNET) as “a tumor with strong invasiveness and rapid growth, which is difficult to treat with surgery, radiation therapy, or drug therapy,” which remains a challenge in the treatment of pituitary tumors. Currently, temozolomide (TMZ) is the first-line treatment for aggressive PitNET. However, it is not yet covered by insurance in Japan. Additionally, O6-Methylguanine-DNA Methyltransferase (MGMT) expression can lead to treatment resistance, further complicating treatment selection. We previously demonstrated the effectiveness of combination therapy with capecitabine (CAPTEM) in several cases of aggressive PitNETs. The present study described our experiences with TMZ in 13 patients with aggressive PitNETs (including four patients administered CAPTEM). Pathological examination revealed eight corticotroph, four lactotroph, and one somatotroph tumors. Of these, seven patients are still receiving treatment, and six patients have terminated treatment. The reasons for discontinuation were poor efficacy (three patients), financial reasons (two patients), and patient preference (one patient). No patients required treatment discontinuation owing to adverse events. Furthermore, one case of a lactotroph tumor, which achieved remission with CAPTEM but was discontinued after three years for financial reasons, remains in remission on imaging and maintained normal PRL levels for 15 months after discontinuation. The most significant issue is off-label use. Concern exists that financial constraints may prevent future patients from using TMZ.

The latest “General Rules for the Description of Thyroid Cancer,” published in 2023, introduced depth-based subcategories of tumor invasion, dividing sEx2 into sEx2a, sEx2b, and sEx3. However, the “Clinical Guidelines on the Management of Thyroid Tumors,” published in 2024, continue to classify these categories uniformly as high-risk for papillary thyroid carcinoma (PTC). We evaluated the appropriateness of reclassifying sEx2a-high-risk patients as intermediate-risk. A total of 9,247 patients [median age: 52 years (7–93)] who underwent locally curative surgery were enrolled, with a median follow-up of 7.8 years. Cause-specific survival (CSS), distant recurrence-free survival (DR-FS), and local recurrence-free survival (LR-FS) worsened progressively from low-risk to high-risk patients. We compared the prognoses among the patients classified as sEx2a-high-risk, sEx2b, and intermediate-risk. The CSS, DR-FS, and LR-FS outcomes of sEx2b patients were significantly poorer than those of sEx2a-high-risk and intermediate-risk patients. By reclassifying sEx2a-high-risk patients as intermediate-risk, we established a new high-risk and intermediate-risk classification. The number of high-risk patients decreased from 2,274 to 1,132, whereas the number of intermediate-risk patients increased from 2,875 to 4,017. Prognoses in these new groups showed minimal differences compared to the original high- and intermediate-risk classifications. We established novel prognostic groups: favorable (N = 6,398, low-risk and intermediate-risk <55 years), intermediate (N = 2,324, intermediate-risk ≥55 years and high-risk <55 years), and poor (N = 525, high-risk ≥55 years). Prognoses significantly worsened across these groups from favorable to poor (p < 0.001). The reclassification of PTC based on tumor extension and the proposed novel prognostic groups provide a more accurate evaluation of PTC outcomes.

The Japan Association of Endocrine Surgery published the first edition of the “Clinical guidelines on the management of thyroid tumors” in 2010 and the revised edition in 2018. The guideline presented herein is the English translation of the revised third edition, issued in 2024. The aim is to enhance health outcomes for patients suffering from thyroid tumors by facilitating evidence-based shared decision-making between healthcare providers and patients, as well as standardizing the management of thyroid tumors. The focus is on adult patients with thyroid tumors, addressing clinically significant issues categorized into areas such as an overview of the diagnosis and treatment of thyroid nodules, treatment strategies by histological type, radioactive iodine therapy, treatment of advanced differentiated carcinoma, pharmacotherapy, and complications and safety management associated with thyroid surgery. Thirty-two clinical questions were established in these areas. Following a comprehensive search of the literature and systematic review to evaluate the overall evidence, we aimed to present optimal recommendations by considering the balance of benefits and harms from the patient’s perspective. We integrated evidence and clinical experience to determine the “Certainty of evidence” and “Strength of recommendations”. Based on these, we illustrated overall flows of care as “Clinical algorithms”. Necessary background knowledge of diseases and established clinical procedures for understanding the recommendations are presented in “Notes”, while information that may be clinically useful but for which evidence remains insufficient is included in “Columns”, based on the current state of evidence. Finally, future challenges for the next revision are presented as “Future research questions”.

Cushing’s disease is a rare endocrine disorder that presents many systemic complications, and its initial phase management can be difficult in atypical and severe cases or at institutes with limited experience. It is a disease in which several complications may have already progressed at the time of diagnosis, and complications may become more severe during the initial management phase, potentially becoming life-threatening. In addition, many patients are young, and depending on this phase management, their quality of life will significantly decline later on. Therefore, this review summarizes the evidence accumulated to date and outlines strategies for disease management, focusing on the initial stages from detection, diagnosis, and referral of patients to surgery.

The random C-peptide and random C-peptide index (CPI) have been shown to be useful in assessing endogenous insulin secretory capacity in adults with type 2 diabetes. This study aimed to clarify the utility of C-peptide and the CPI in early classification of long-term insulin-dependent status in pediatric diabetes patients. A total of 204 patients aged ≤15 years who received an initial diagnosis of acute-onset type 1 diabetes mellitus (T1DM), slowly progressive insulin-dependent diabetes mellitus (SPIDDM), or type 2 diabetes mellitus (T2DM) at Yokohama City University Medical Center between April 1, 2003 and March 31, 2018 were included. The acute-onset T1DM, SPIDDM, and T2DM groups included 140, 8, and 56 patients, respectively. The median random C-peptide values were 0.67, 3.18, and 4.16 ng/mL and median random CPI values were 0.19, 2.02, and 2.53 for acute-onset T1DM, SPIDDM, and T2DM cases, respectively (acute-onset T1DM vs. T2DM, p < 0.001 (C-peptide), p < 0.001 (CPI), acute-onset T1DM vs. SPIDDM, p < 0.001 (C-peptide), p < 0.001 (CPI), SPIDDM vs. T2DM, p = 0.04 (C-peptide), p = 0.19 (CPI)). Receiver operating characteristic analysis cutoff values of C-peptide levels in differentiating acute-onset T1DM from SPIDDM and acute-onset T1DM from T2DM were 1.60 ng/mL (sensitivity 87.5%, specificity 90.6%) and 1.81 ng/mL (sensitivity 91.1%, specificity 93.5%), while the respective CPI values were 0.46 (100% sensitivity, 77% specificity) and 1.05 (92.1% sensitivity, 87.5% specificity). This study indicates that the random C-peptide and random CPI at diagnosis are helpful in the early classification of childhood diabetes and determining an appropriate time to introduce insulin and predicting the subsequent clinical course.

To determine the prognosis of Graves’ disease initially presenting with severe subclinical hyperthyroidism, we investigated 110 patients with Graves’ disease with normal FT3 and FT4 levels and TSH below 0.1 μU/mL. Graves’ disease was diagnosed based on the diffuse accumulation of radioiodine in the thyroid in 83 patients, while the other 27 patients were diagnosed based on positive anti-TSH receptor antibodies. Seventy patients did not receive immediate medical treatment for the hyperthyroidism. Forty-four patients developed overt hyperthyroidism after 1–131 (median 3) months. In 19 patients, TSH levels returned to normal after 1–43 (median 6) months. One patient developed persistent hypothyroidism after two months, and another six had subclinical hyperthyroidism during the observation period. The positivity of TSH receptor antibodies was significantly higher (p = 0.0445) in patients who developed overt hyperthyroidism (86.0%) than in other patients (65.4%). Seventeen patients were treated immediately after diagnosis. Seven patients remitted after 2–94 (median 9) months of medical treatment. Another 10 patients remained euthyroid under the continuous administration of small amounts of medication. Some patients with severe subclinical hyperthyroidism due to Graves’ disease develop overt hyperthyroidism. If patients are at risk due to cardiovascular diseases, osteoporotic fractures, or an older age, then immediate treatment can be considered. Otherwise, careful monitoring of the thyroid function without treatment for 6 months is considered to be reasonable. TRAb has been suggested to play a role in the progression of subclinical hyperthyroidism due to Graves’ disease.

This study investigated the role of scutellarin (Scu) and Nrf2 in diabetic atherosclerosis, focusing on their effects on FBXL2 and NLRP3 ubiquitination. Human umbilical vein endothelial cells were treated with high glucose (HG) to model diabetic atherosclerosis in vitro. Cell viability, cytotoxicity, pyroptosis, and inflammatory cytokine levels were assessed, and gene interactions were examined by dual-luciferase reporter assays. Ubiquitination and protein levels were analyzed through immunoprecipitation and western blotting. The results revealed that HG treatment decreased Nrf2 and FBXL2 levels and enhanced NLRP3-mediated pyroptosis. However, Scu treatment increased Nrf2 expression, improved cell viability, and inhibited pyroptosis. Nrf2 knockdown downregulated FBXL2 and reversed the protective effects of Scu. Additionally, FBXL2 promoted the ubiquitination-mediated degradation of NLRP3 and suppressed pyroptosis. The activation of NLRP3 reversed the protective effects of Scu on diabetic atherosclerosis. These findings suggest that Scu alleviated diabetic atherosclerosis by increasing Nrf2 and FBXL2 expression, promoting NLRP3 ubiquitination-mediated degradation, and suppressing pyroptosis.

Hyperuricemia reflects increased insulin resistance, and uric acid (UA) may serve as a predictive marker for the development of metabolic dysfunction-associated steatotic liver disease (MASLD); however, few studies have investigated this condition in the Japanese population. Thus, this retrospective observational study aimed to investigate the association of hyperuricemia with the risk of MASLD or metabolic and alcohol-related liver disease (MetALD) in individuals undergoing health checkups. A cross-sectional analysis was performed on 58,110 individuals, dividing them into quartile groups according to UA values for men and women (Q1 being the lowest and Q4 being the highest), and examining the complication rate of MASLD/MetALD. Subsequently, among 22,364 individuals without MASLD/MetALD, the relationship between UA at baseline and MASLD/MetALD development during follow-up was investigated using Cox proportional hazard models. In the cross-sectional analysis, the higher UA group had a higher complication rate of MASLD/MetALD in both men and women. In the follow-up analysis, both genders in the higher UA quartiles had a significantly higher incidence of MASLD/MetALD than those in the lower quartiles. Multivariate Cox proportional hazards analysis revealed that Q4 had a significantly higher hazard ratio than Q1 for both genders. These trends were the same in the time-dependent body mass index (BMI) model, which incorporated BMI as a time-dependent variable. High UA levels may serve as a predictive marker for MASLD/MetALD development. UA monitoring during health checkups could enable early detection and provision of intervention, improving patient outcomes.

Inorganic iodine has long been used as a treatment for Graves’ disease. It is currently a treatment option for mild Graves’ disease, but there have been no data suggesting the validity of continuing low-dose iodine treatment after improvement in thyrotoxicosis. For this prospective observational study, we recruited patients with Graves’ disease treated only with low-dose iodine (potassium iodine ≤25 mg/day). These patients were then divided into two groups: those who continued with low-dose iodine (C group) and those who discontinued it (DC) group. We compared the 2-year thyrotoxicosis relapse rate between the two groups and investigated anthropometric variables associated with relapse. Of 2,159 patients on iodine treatment, 56 patients met the selection criteria but 4 who gave consent dropped out, leaving 25 in the C group and 27 in the DC group. Regarding baseline characteristics, the C group had a longer duration of Graves’ disease, lower therapeutic iodine doses, and lower TSH levels than the DC group. During the 2-year follow-up period, the relapse rate in the C and DC groups was 32.0% and 22.2%, respectively (p = 0.536). Furthermore, patients who relapsed had significantly higher therapeutic iodine doses, FT4 levels, and TSAb levels at baseline than patients who did not relapse. Multiple logistic regression showed that relapse is positively associated with therapeutic iodine dose and TSAb levels. The present study failed to show the efficacy of continuing low-dose iodine in patients with Graves’ disease after improvement in thyrotoxicosis. The relapse rate seems to be affected by residual immune activity. UMIN000047660

Limited real-world data are available on persistence to growth hormone replacement therapy (GHRT) in Japan. Therefore, we used the Japan Medical Data Center claims database to retrospectively investigate persistence with GHRT in patients with pediatric growth hormone deficiency (pGHD). We identified 1,020 patients with pGHD treated with GHRT. The mean age at initial diagnosis was 7.5 ± 3.8 years, and we found a bimodal pattern in age, with peaks at 3 and 12 to 13 years of age; the peaks were more pronounced in male patients. After excluding patients with early withdrawal, 1,016 patients were eligible for persistence analysis. The time to initial treatment discontinuation, i.e., the first prescription-free period of 182 days (6 months) or more, for 50% of the patients was 2,526 days, which was similar to that of treatment completion (2,626 days). Most patients persisted with GHRT until they completed treatment, but 24 out of 1,016 (2.4%) had a treatment discontinuation. The mean proportion of days covered was 89.8%. Being female (hazard ratio [95% CI]: 1.85 [1.36–2.51]) and older age at diagnosis (1.50 [1.41–1.60]) were associated with shorter time to discontinuation. This finding suggests that most patients persist with GHRT until puberty. In conclusion, although most Japanese patients with pGHD appear to persist well with GHRT, some complete GHRT before puberty. Additionally, there are patients diagnosed and starting treatment just before puberty. Therefore, continued efforts towards early referral and diagnosis are important.

High-mobility group AT-hook 2 (HMGA2) is a nuclear protein involved in the differentiation and proliferation of epithelial-derived tumors and also considered to be involved in the growth and differentiation of various malignant tumors, including thyroid cancer. Immunohistochemistry (IHC) for HMGA2 has been reported to show diffuse positivity in several follicular thyroid carcinoma (FTC) cases. This study aimed to investigate whether positive immunohistochemical staining for HMGA2 in primary tumors can be used to predict the prognosis and detect prognostic factors in malignant thyroid tumors associated with metastatic recurrence in FTC. Formalin-fixed, paraffin-embedded (FFPE) resected specimens used for the IHC for HMGA2. The association of positive HMGA2 staining with metastasis and recurrence, along with the potential of HMGA2 as a prognostic marker of metastatic recurrence, was statistically determined. HMGA2 staining was positive in most malignant tissues, whereas benign tissues were unstained. HMGA2 staining of the marginal and invasive regions was observed in FTC tissues. The association of HMGA2 staining with metastasis and recurrence was significant (p = 0.018). Kaplan-Meier curves showed an association of negative HMGA2 staining with metastasis and disease-free survival (p = 0.090). Tumor size (>4 cm) and wide invasion were also significant factors (p = 0.043, p < 0.001). The risk ratio without HMGA2 was significantly reduced by 30% compared to that with HMGA2. In primary tumors, positive HMGA2 staining can be used to predict prognosis in malignant thyroid tumors associated with metastatic recurrence in FTC and negative HMGA2 staining may indicate longer disease-free survival after surgery.

Pheochromocytomas occur in the adrenal medulla and present with various symptoms associated with excessive catecholamine production. Although pheochromocytomas associated with ectopic ACTH-producing tumors and hyper-interleukin-6emia (hyper-IL-6emia) have been reported, those associated with both diseases simultaneously have not been reported. In pheochromocytomas with ectopic ACTH-producing tumors and hyper-IL-6emia, the disease characteristics and relationship between each hormone and cytokine are unknown. Herein, we report a case of a 56-year-old woman with stroke whose computed tomography scans of the abdomen revealed a right adrenal tumor on systemic examination. Endocrinological examination revealed elevated plasma levels of catecholamines and their metabolites in the urine and elevated levels of plasma ACTH, serum cortisol, and serum dehydroepiandrosterone sulfate, leading to a diagnosis of right pheochromocytoma and associated ectopic ACTH-producing tumor. Furthermore, hyper-IL-6emia was detected as a key indicator of anemia due to inflammatory hematopoietic disorders. The patient’s general condition improved with drug therapy, including 1,000 mg/d of metyrapone, 2 mg/h of phentolamine, 8 mg/d of doxazosin, and systemic management. Dexamethasone suppression tests demonstrated suppressed serum cortisol and IL-6 levels, and dexamethasone dose-dependently increased plasma adrenaline and noradrenaline levels. These findings indicate that excess glucocorticoids play a stimulatory role in catecholamine secretion and a concentration-suppressive role in serum IL-6 levels in pheochromocytomas associated with ectopic ACTH-producing tumors and hyper-IL-6emia. The presence of rare comorbidities should be considered if the clinical findings cannot be explained by the pathophysiology of a pheochromocytoma alone because pheochromocytomas can be associated with the production of other hormones and cytokines.

The prevalence of obesity is increasing rapidly worldwide, particularly in Asia. Visceral obesity, characterized by intra-abdominal fat accumulation, is a precursor to metabolic syndrome, encompassing hyperglycemia, dyslipidemia, and hypertension, which elevate the risk of atherosclerosis and cardiovascular disease. A visceral fat area (VFA) of ≥100 cm² is a recognized threshold for diagnosing obesity-related metabolic syndrome. This study aimed to identify independent risk factors for VFA ≥100 cm² in middle-aged Chinese individuals from the general population. We analyzed data from 148 participants (mean age: 49.3 ± 10.8 years; 54% male) who underwent health check-ups. VFA and subcutaneous fat area were assessed using computed tomography, while arterial stiffness and fatty liver were evaluated via brachial-ankle pulse wave velocity (baPWV) and abdominal ultrasonography, respectively. Between-group comparisons (VFA ≥100 cm² vs. VFA <100 cm²) were conducted using unpaired t-tests and Mann-Whitney U tests, and logistic regression analysis identified risk factors. Multivariable regression analysis revealed that baPWV ≥1,400 cm/s (odds ratio [OR] = 5.71, p = 0.011), waist circumference ≥85 cm (OR = 5.46, p = 0.026), fasting blood glucose (FBG) ≥100 mg/dL (OR = 5.69, p = 0.030), male sex (OR = 12.79, p = 0.029), and fatty liver (OR = 3.99, p = 0.042) were significant independent risk factors for VFA ≥100 cm². Among these, baPWV ≥1,400 cm/s was the most significant, showing a positive correlation with VFA (r = 0.365, p < 0.001). Visceral obesity (VFA ≥100 cm²) is a critical target for interventions addressing metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and cardiovascular disease, particularly in males.

In Japan, the guidelines for gestational weight gain (GWG) were revised in 2021. Under the new guidelines, pregnant women are recommended to increase their GWG. The aim of this study was to compare the incidence of adverse pregnancy outcomes (APOs), large for gestational age (LGA), and postpartum glucose tolerance in gestational diabetes mellitus (GDM) patients before and after the revised GWG standards. This retrospective cohort study enrolled 1,021 GDM patients who underwent prenatal glycemic control and a postpartum 75-g oral glucose tolerance test. The endpoint was the incidence of APOs, LGA, and postpartum impaired glucose tolerance (IGT) and diabetes mellitus (DM). There was no significant difference in the incidence of APOs and postpartum IGT and DM in GDM patients before and after the revised GWG standards. On the other hand, when the new GWG standards were applied to GDM patients, the incidence of LGA increased (adjusted odds ratio [aOR]; 1.764, 95% confidence interval [CI]; 1.180–2.637). In particular, when classified by pre-pregnancy body mass index, the incidence of LGA increased in the obese group (aOR; 5.944, 95% CI; 1.847–19.129). Future prospective cohort studies are needed to verify the efficacy and safety of appropriate GWG in Japanese GDM patients.

Serum thyroglobulin (Tg) levels are highly sensitive and specific tumor markers in patients with thyroid cancer who have undergone total thyroidectomy and radioiodine (RAI) therapy. Recently, we reported a case wherein serum Tg levels fluctuated according to hemoglobin A1c (HbA1c) levels, demonstrating a strong correlation between serum Tg and HbA1c levels. However, whether this association exists broadly in other patients with thyroid cancer remains unclear. Therefore, we retrospectively investigated this association in six patients with thyroid cancer and diabetes who underwent total thyroidectomy and RAI therapy at our institution. Two patients exhibited a significant correlation between serum Tg and HbA1c levels (r = 0.53, p < 0.01 and r = 0.66, p = 0.01). In these patients, a gradual decrease in serum Tg levels was observed, along with improved glycemic control. Two other patients showed a non-significant correlation between serum Tg and HbA1c levels (r = 0.72, p = 0.11 and r = 0.54, p = 0.17). In these patients, a rapid increase in serum Tg levels was observed, with HbA1c levels showing only small fluctuations. In the remaining two patients, no correlation was found; in these patients, the fluctuations in serum Tg levels were only small, despite fluctuations in HbA1c levels. In conclusion, serum Tg levels may be associated with HbA1c levels in some patients with thyroid cancer and diabetes. The correlation between serum Tg and HbA1c levels was more evident in patients with gradual fluctuations in Tg levels. Future studies with larger cohorts are necessary to clarify the underlying mechanism by which glycemic control influences Tg levels and establish appropriate monitoring methods.

We investigated the association between a 500 MBq dose of radioactive iodine treatment (RAIT) and both thyroid nodule volume and thyroid function in patients with a single autonomous functioning thyroid nodule (AFTN). We retrospectively studied 201 patients with an AFTN who received RAIT at a dose of 500 MBq and were followed up for more than 2 years. Thyroid function at diagnosis, thyroid antibody positivity, treatment with antithyroid drugs before RAIT, cystic components of the nodule, and ¹³¹I uptake outside the nodule were assessed. Nodule enlargement was observed in 18 patients (9%), persistent hyperthyroidism in 13 patients (6.5%), and hypothyroidism in 45 patients (22.3%). Nodule volume before RAIT was significantly larger in the nodule enlargement group compared to the non-enlargement group. The risk factors for persistent hyperthyroidism were larger nodule volume and absence of a cystic component in multivariate analysis. The cutoff nodule volume before RAIT for predicting nodule enlargement was 15.5 mL, and for predicting persistent hyperthyroidism was 16.6 mL. Nodule volume decreased to 47% in the first year and continued to gradually decrease thereafter. This study provided long-term outcome data regarding nodule volume change and thyroid function in AFTN patients following single fixed-dose RAIT, and it identified risk factors for nodule enlargement and persistent hyperthyroidism after RAIT. Nodule volume before treatment was a good predictor of treatment response.