Pheochromocytomas and paragangliomas are characterized by two key features: endocrine disorders with excessive catecholamine secretion and a hereditary or metastatic nature, making early diagnosis and treatment crucial. This clinical practice guideline is a revision of the 2018 edition, which considers recent advances in clinical practice and changes to the health insurance coverage in Japan. Patients presenting with symptoms such as palpitations, headaches, hypertension, or abdominal tumors should undergo screening and confirmation with measurement of fractionated catecholamines and their metabolites in the blood and urine. When the tumor is located in the adrenal glands, it is diagnosed as a pheochromocytoma; when it is located outside the adrenal gland and confirmed by ¹²³I-MIBG scintigraphy or ¹⁸F-FDG PET, it is diagnosed as a paraganglioma. Treatment begins with inhibiting catecholamine action using α-blockers, and if that is insufficient, metyrosine is used in combination, followed by laparoscopic tumor removal. Given the metastatic potential, long-term postoperative follow-up is essential. Even in cases of metastasis, tumor debulking should be considered. Treatment options are selected based on the amount of remaining tumor, symptom severity, and lesion progression, including CVD chemotherapy or radionuclide therapies such as ¹³¹I-MIBG or ¹⁷⁷Lu-DOTATATE. Genetic testing guides the management of different variants, and significant progress has been made in molecularly targeted drug trials. Therefore, further advances in individualized and long-term management are required.

The incidence of immune checkpoint inhibitor (ICI)-induced type 1 diabetes mellitus (ICI-T1DM) has increased as the use of ICIs has increased. Autoimmune ICI-T1DM often presents as diabetic ketoacidosis, resulting from insulin deficiency, among which insulin resistance is extremely rare. Here, we describe a patient with advanced myxoid liposarcoma who developed sintilimab-induced fulminant autoimmune diabetes associated with insulin resistance and metabolic disorders. The patient eventually required the combined use of insulin, metformin, liraglutide, and dapagliflozin to reduce blood glucose due to erratic glycaemic excursions and high insulin requirements during his duration of hospital stay. Metformin, dapagliflozin and liraglutide were discontinued because of weight loss half a year after discharge, and intensive insulin therapy was continued. The patient’s blood glucose control was poor, and liraglutide and metformin were then added again, half a year later. Together, metformin, dapagliflozin and liraglutide in combination with insulin may help control blood glucose in ICI-induced DM patients with insulin resistance.

GPR75 has emerged as a therapeutic target for obesity following the discovery of a causal relationship between GPR75 variants and reduced body mass index in humans. Herein, we examined whether GPR75 is dispensable for normal feeding, body growth, and reproduction using newly generated Gpr75 knockout (KO) rats fed normal chow. Gpr75 was highly expressed in the brain, including several hypothalamic nuclei, in rats of both sexes. Gpr75 KO male and female rats exhibited significantly lower food intake, reduced feeding duration during the dark phase, and lower body weight (BW) than wild-type rats. Importantly, Gpr75 KO did not affect reproduction in either sex, including puberty onset, pulsatile luteinizing hormone secretion, or litter size. We also examined the effects of Gpr75 KO on hyperphagia, obesity, hyperglycemia, and hyperinsulinemia in male rats on a high-fat diet (HFD). HFD-fed Gpr75 KO male rats exhibited significantly lower food intake, BW, and fat accumulation than wild-type rats and were normoglycemic and normoinsulinemic. Notably, hypothalamic Ccl5 (encoding C-C motif chemokine ligand 5 [CCL5]) expression was significantly higher in Gpr75 KO male rats than in wild-type rats, suggesting that Gpr75 KO may prevent HFD-induced hyperphagia via central CCL5 signaling in rats. Thus, GPR75 signaling, although dispensable for reproduction, contributes to feeding and body growth in rats on normal chow and is involved in HFD-induced hyperphagia, obesity, hyperglycemia, and hyperinsulinemia development. Therefore, GPR75 antagonism may offer a potential therapeutic approach to control feeding and BW and prevent obesity and insulin resistance without affecting reproduction in humans.

Few studies have investigated the distribution of blood pressure (BP) and associated factors in pediatric patients with X-linked hypophosphatemic rickets (XLH). We analyzed snapshot baseline data from the SUNFLOWER study, a longitudinal observational cohort study of patients with XLH in Japan and South Korea (NCT03745521/UMIN000031605). We used data from pediatric participants aged 5–17 years who were 120–189.9 cm (males) and 120–179.9 cm (females) in height and had a history of conventional treatment. Systolic and diastolic BP (SBP and DBP, respectively) were categorized into percentile ranks based on age, sex, and height. Ordinal logistic regression analyses were performed to investigate the association between BP and exposure factors, including estimated glomerular filtration rate, serum intact parathyroid hormone levels, serum intact fibroblast growth factor 23 levels, urinary calcium/creatinine ratio, and body mass index standard deviation score (BMI-SDS). Forty-five participants were eligible for the subgroup analysis. Of these, 44 were evaluated after one patient with missing BP data was excluded. After height adjustment, three patients (6.8%) were at or above the 95th percentile for SBP, and five (11.4%) were at or above the 95th percentile for DBP. Regarding age adjustment, one patient (2.3%) was at or above the 95th percentile for SBP and three (6.8%) were at or above the 95th percentile for DBP. In the association analysis, age- and height-adjusted BP was positively correlated with BMI-SDS. These results suggest that some pediatric patients with XLH exhibit high BP and that a high BMI-SDS may be a risk factor.

Medullary thyroid carcinoma (MTC) can occur sporadically or as a hereditary disease. The latter often presents with a multiple endocrine neoplasia type 2 (MEN2) phenotype and is caused by germline-activating pathogenic variants in the RET proto-oncogene, whereas the former may harbor somatic-activating RET pathogenic variants. Here, we report a family with a germline RET V778I pathogenic variant. The proband was a 72-year-old woman with bilateral multifocal MTCs but without other MEN2 features. Germline RET analysis revealed a homozygous V778I pathogenic variant. Postoperative histopathological examination confirmed bilateral multifocal MTC with lymph node metastasis. The patient’s parents were cousins. The patient had no family history of MTC or MEN2. Her three middle-aged children were heterozygous for the V778I pathogenic variant, had no symptoms or signs of MTC, and had normal serum calcitonin and CEA levels. The proband died of cardiac and pulmonary diseases at the age of 86, 15 years after surgery, without MTC recurrence. Unlike other dominant RET pathogenic variants, in which a single mutated allele is sufficient for tumor development, V778I may have weak oncogenic activity, requiring homozygosity to develop MTC. Therefore, prophylactic thyroidectomy is not recommended for heterozygous carriers. To the best of our knowledge, this is the second report of a family with MTC exclusively associated with a homozygous RET pathogenic variant. This is also the first report of a germline RET V778I pathogenic variant associated with MTC under homozygous conditions.

The impact of changes in obesity-related parameters on kidney functions is unclear. To evaluate the association of body weight (BW) and waist circumference (WC) changes with estimated glomerular filtration rate (eGFR) and proteinuria in obese individuals, we conducted retrospective analysis of the Japan Specific Health Checkup cohort of 664,926 participants (Japanese residents aged 40–74 years) from 2008 to 2011. Participants were classified into nine groups based on BW and WC changes from baseline. Sex differences were stratified. Generalized estimating equations were used to evaluate eGFR changes within each group and the effect of BW or WC changes on eGFR. In a similar manner, the impact of BW and WC changes on the incidence of proteinuria was measured. As a result, total of 20,326 participants with a body mass index of ≥25 kg/m² and available baseline data, 1-year BW and WC, and 4-year eGFR measurements were included in the analysis. The eGFR slope was –0.59 (95% confidence interval [CI], –0.66 to –0.51). At a threshold change of approximately 5%, compared to the group with unchanged BW and WC, males with decreased BW and WC had improved eGFR at 3 years (1.75; 95% CI, 0.49 to 3.02). Contrastingly, females with increased BW and WC had worsened eGFR at 3 years (–3.44; 95% CI, –6.40 to –0.47). These trends were similar when the thresholds were changed or when the outcome was proteinuria. In conclusion, males with decreasing WC and BW had improved kidney function. Future studies should evaluate specific lifestyle factors.

Some patients with Graves’ disease (GD) develop hypothyroidism after antithyroid drug (ATD) treatment and are found to be positive for thyroid stimulation-blocking antibody (TSBAb). However, thyroid volume (TV) changes throughout this process remain unclear. Therefore, we aimed to quantify TV changes before and after hypothyroidism onset in patients with GD harboring TSBAb and compare them with those in patients with GD who developed hypothyroidism without TSBAb or achieved remission with ATD. This retrospective study evaluated TV changes using ultrasonography in three groups: 10 patients with GD who developed hypothyroidism with TSBAb (TSBAb(+)-hypo group), nine without TSBAb (TSBAb(–)-hypo group), and 91 who achieved remission after ATD treatment (Remission group). In the TSBAb(+)-hypo group, TV significantly decreased from the hyperthyroid to hypothyroid phase (median: 33.3 mL [range: 14.2–52.0] vs. 13.6 mL [4.3–23.3], respectively; p = 0.001). In the TSBAb(–)-hypo group, TV significantly decreased from the hyperthyroid to hypothyroid phase (26.6 mL [11.9–49.2] vs. 20.9 mL [7.4–34.2], respectively; p = 0.037). In the Remission group, TV also decreased significantly from the hyperthyroid to remission phase (29.8 mL [8.2–88.4] vs. 25.1 mL [9.5–72.0], respectively; p = 0.0002). The decrease in TV was significantly higher in the TSBAb(+)-hypo group than in the TSBAb(–)-hypo and Remission groups (53.9% [37.9–74.5] vs. 30.9% [–22.3 to 63.0] and 10.7% [–100.7 to 52.0], respectively; p = 0.027 and <0.0001). This study documents the first precise measurement of TV reduction using ultrasonography in patients with GD who developed hypothyroidism with TSBAb, showing a markedly greater decrease than in those without TSBAb or in remission after ATD treatment.

This study aimed to investigate the association between body composition and lung function. Metabolic body composition can independently predict the risk of poor lung function. Accordingly, this cross-sectional observational study included adults aged ≥18 years who attended annual health examinations at Xiamen Chang-Gung Hospital from 2013 to 2016. The study evaluated the association between lung function and metabolic body composition, after correcting for possible influencing factors. Males had a higher body mass index and waist-to-hip ratio and a higher prevalence of smoking and drinking histories. Additionally, men showed significantly higher mean arterial pressure, fasting blood glucose, total cholesterol, triglyceride, low-density lipoprotein cholesterol, insulin, and homeostasis model assessment for insulin resistance values than those of women (all p < 0.001). The proportion of metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) was also higher in men than in women (17.91% vs. 25.20% and 11.28% vs. 13.67%, respectively). However, female participants demonstrated better pulmonary function. The prevalence of restrictive lung disease (RLD) was substantially higher in men than in women. The study findings suggest that MUO, and to a lesser extent, metabolic obesity with normal weight (MONW), are independent risk factors for RLD. These results imply that MUO, and to a lesser extent, MONW, may serve as potential screening markers for preclinical RLD in annual health checkups.

East Asians are known to develop diabetes mellitus at a lower body weight than Caucasians, potentially because of the different mechanisms underlying disease development. This study aimed to evaluate the variation in weight transition leading to diabetes onset in two subtypes of individuals (obese and non-obese) in a Japanese population. We conducted a retrospective, observational, longitudinal cohort study using health checkup data from 9, 260 participants in Japan. Individuals who developed diabetes within three years of the start of the observation period were excluded. Among the participants, 61.4% were men, and 259 developed diabetes. In the obesity group (body mass index [BMI] ≥25 kg/m²), the average BMI increased prior to the diabetes onset and subsequently decreased. Conversely, in the non-obesity group (BMI <25 kg/m²), the average BMI decreased and then stabilized before the onset of diabetes. Notably, a greater number of participants in the non-obesity group exhibited a BMI change of ≤–0.15 kg/m² per year compared with those with a BMI change of ≥0.15 kg/m² per year before diabetes onset (p = 0.003). Our findings indicate that body weight loss precedes the onset of diabetes in the non-obesity group. We recommend that non-obese individuals with elevated blood glucose levels who do not meet the criteria for diabetes should be considered a high-risk group for diabetes development. Therefore, it is imperative to identify these individuals and provide lifestyle guidance that does not focus on weight loss to prevent the onset of diabetes.

We report the case of a 50-year-old female diagnosed with primary aldosteronism (PA) complicated with mild autonomous cortisol secretion (MACS). The patient had a 5-year history of hypertension, and screening revealed an elevated aldosterone-to-renin ratio (ARR). Although she demonstrated no clinical features of Cushing’s syndrome, her serum potassium level was at the lower end of the normal range. The baseline plasma renin activity was <0.2 ng/mL/h, and the plasma aldosterone concentration was 165 pg/mL. Confirmatory tests supported the diagnosis of PA, and computed tomography (CT) revealed a 19-mm tumor in the left adrenal gland. Following a 1-mg dexamethasone suppression test, her serum cortisol level measured 9.0 μg/dL, and the diurnal rhythm of cortisol secretion was absent. Plasma adrenocorticotropic hormone (ACTH) was suppressed. Adrenal venous sampling (AVS) revealed right-sided dominance before and after ACTH stimulation, with lateralization indices of 43.8 and 5.0, respectively. Considering the findings, we prioritized treatment for MACS and performed left adrenalectomy. Hypertension and elevated ARR persisted postoperatively. Histopathological examination revealed a 26-mm CYP11B-positive and CYP11B2-negative adenoma. The surrounding adrenal cortex contained multiple CYP11B1-negative and CYP11B2-positive nodules and micronodules. This case was retrospectively considered to represent bilateral PA. The AVS interpretation was misleading owing to cortisol imbalance between the adrenal veins due to cortisol producing adenoma. Treatment strategies for patients with PA and concurrent MACS should encompass a comprehensive assessment of AVS and CT findings.

GPT-4o, a general-purpose large language model, has a Retrieval-Augmented Variant (GPT-4o-RAG) that can assist in dietary counseling. However, research on its application in this field remains lacking. To bridge this gap, we used the Japanese National Examination for Registered Dietitians as a standardized benchmark for evaluation. Three language models—GPT-4o, GPT-4o-mini, and GPT-4o-RAG—were assessed using 599 publicly available multiple-choice questions from the 2022–2024 national examinations. For each model, we generated answers to each question five times and based our evaluation on these multiple outputs to assess response variability and robustness. A custom pipeline was implemented for GPT-4o-RAG to retrieve guideline-based documents for integration with GPT-generated responses. Accuracy rates, variance, and response consistency were evaluated. Term Frequency–Inverse Document Frequency analysis was conducted to compare word characteristics in correctly and incorrectly answered questions. All three models achieved accuracy rates >60%, the passing threshold. GPT-4o-RAG demonstrated the highest accuracy (83.5% ± 0.3%), followed by GPT-4o (82.1% ± 1.0%), and GPT-4o-mini (70.0% ± 1.4%). While the accuracy improvement of GPT-4o-RAG over GPT-4o was not statistically significant (p = 0.12), it exhibited significantly lower variance and higher response consistency (97.3% vs. 91.2–95.2%, p < 0.001). GPT-4o-RAG outperformed other models in applied and clinical nutrition categories but showed limited performance on numerical questions. Term Frequency–Inverse Document Frequency analysis suggested that incorrect answers were more frequently associated with numerical terms. GPT-4o-RAG improved response consistency and domain-specific performance, suggesting utility in clinical nutrition. However, limitations in numerical reasoning and individualized guidance warrant further development and validation.

Lenvatinib is approved for the first-line treatment for radioiodine-refractory differentiated thyroid cancer (RR-DTC) at a starting dose of 24 mg/day, but its high toxicity often necessitates dose reductions and interruptions. To clarify the efficacy and safety of the reduced dose-initiation of lenvatinib, especially for smaller-build and/or frail Asians, we retrospectively examined outcomes of 43 Japanese individuals with RR-DTC who were treated with lenvatinib, focusing on the initial dose. Twenty-three patients initiated lenvatinib at a full-dose (24 mg/day) and 20 patients initiated at a reduced-dose (≤14 mg/day). In the full dose-initiation group, 14 of 23 (60.8%) patients required discontinuation of lenvatinib within ~30 days due to adverse effects, which was significantly higher rate compared to that (25.0%) of the reduced dose-initiation group (p = 0.018), and 5 patients of the full dose-initiation group did not resume treatment. Compared to the full dose-initiation group, the reduced dose-initiation group were older (nonsignificant) and had significantly lower body weights, lower overall daily dose exposure, and a lower frequency of adverse events (≥grade 2) but a comparable dose interruption rate and daily dose exposure per kg during overall observation period. In multivariate analyses for progression-free survival and overall survival, malignant pleural effusion and symptomatic metastases but not the starting dose of lenvatinib were significantly associated with worse outcomes. Initiating lenvatinib at a reduced dose based on patients’ physical status may be an option, with not only lower adverse events but also efficacy comparable to that of the full dose.

The ectopic intrathyroidal thymus (EIT) is located anywhere in the thyroid gland along the developmental pathway of thymic descent due to thymic migration during embryogenesis. Ultrasonographic findings of papillary thyroid carcinoma (PTC) resemble those of EIT, which is frequently found in children. We comprehensively evaluated the clinical factors associated with EIT to understand its physiological implications and to explore helpful information for clinical discrimination between EIT and PTC. Approximately 320,000 datasets of thyroid ultrasound examinations conducted in the Fukushima Health Management Survey were systematically analyzed. Trend analyses were performed following stratification into groups of the age-sex-adjusted standard deviation score (SDS) for body mass index (BMI-SDS) and body surface area-sex-adjusted SDS for both the width and thickness of the area (BWTAR) as an indicator of thyroid volume (BWTAR-SDS). The prevalence of EIT was 3.2% in the study. Compared with negative EIT, the age- and sex-adjusted odds ratios (95% confidence intervals) for the BMI-SDS, BWTAR-SDS, and presence of diffuse goiter, cysts, and nodules were 0.919 (0.901–0.939), 0.976 (0.957–0.996), 0.821 (0.602–1.121), 0.892 (0.853–0.932), and 1.602 (1.302–1.972), respectively. EIT was not associated with the presence of diffuse goiter but was independently associated with male sex, young age, small thyroid volume, low BMI, absence of cysts, and presence of nodules. The series of clinical factors related to EIT shown in the study might provide complementary information in addition to ultrasonographic findings in cases with asymptomatic thyroid nodules resembling PTC found in young patients.

Steroidogenesis inhibitors such as metyrapone and osilodrostat, target 11β-hydroxylase to inhibit cortisol synthesis, are used in inoperable or recurrent Cushing disease. While osilodrostat has been reported to be more effective at lower doses than metyrapone, there are only a few reports describing the difference between osilodrostat and metyrapone in clinical practice. In this study, we evaluated the changes in steroid hormone profiles and clinical outcomes in seven Cushing disease patients switched from metyrapone to osilodrostat after incomplete remission post-transsphenoidal sinus surgery. Three of the seven patients were using trilostane, which was discontinued at the same time as metyrapone. Steroid hormone concentrations, including cortisol, progesterone (Prog), pregnenolone (Preg), deoxycorticosterone, corticosterone, 17-hydroxyprogesterone (17Prog), 17-hydroxypregnenolone (17Preg), and 11-deoxycortisol, were measured using high-performance liquid chromatography–mass spectrometry. No adverse events occurred after switching to osilodrostat. Potassium and ACTH levels increased significantly, and dehydroepiandrosterone sulfate and testosterone levels decreased significantly. Cortisol levels did not change significantly, whereas the ratios reflecting CYP17A1 activity (17Preg/Preg and 17Prog/Prog) decreased significantly, suggesting superior inhibition of CYP17A1 with osilodrostat. Clinical improvements included reduced antihypertensive medication requirements, decreased masculinization, and resolved gastric discomfort. Different inhibition patterns of the steroid synthetic enzymes may explain the observed clinical outcomes between these drugs. These data suggest that in patients with Cushing disease receiving metyrapone, switching to osilodrostat may benefit cases with inadequate disease control and complications including hypertension, manifestation of masculinization, and gastric discomfort.

Urinary calcium excretion increases in patients with primary aldosteronism (PA) and is associated with higher prevalence of renal stones formations. However, it remains unclear whether the prevalence of urinary stones is higher in patients with PA than in those with nonfunctioning adrenal tumors (NF). We aimed to investigate whether the prevalence of urinary stones is higher in patients with PA than in those without PA. The study was conducted between April 2006 and March 2021. We enrolled 140 PA and 144 NF patients. Urinary stones and renal calcifications were evaluated through patient history or CT findings. Serum and urinary parameters, presence of urinary stones and/or calcifications, were evaluated in both groups. Logistic regression analyses were performed, adjusting for relevant variables. Compared to the NF group, the PA group was younger, and displayed significantly higher blood pressure, aldosterone-rennin ratio, eGFR, serum Na, urinary Ca excretion, and intact PTH levels. In contrast, serum K, Ca and creatinine levels were lower in PA group. PA patients also demonstrated a lower prevalence of diabetes, smaller adrenal tumor size, and a lower percentage of smokers compared to the NF group. Urinary stones and renal calcifications were significantly more frequent in the PA group. Logistic regression confirmed PA as an independent risk factor for urinary stones, regardless of age, sex, BMI, eGFR, serum and urinary calcium, and intact PTH. PA is an independent risk factor for urinary stones and renal calcifications.

Patients with primary hyperparathyroidism (PHPT) ineligible for surgery require medical management for hypercalcemia and osteoporosis. The aim of this retrospective study was to determine the long-term effects of evocalcet on serum corrected calcium (cCa) levels and bone mineral density (BMD) in PHPT. The study included 26 patients with PHPT and hypercalcemia treated with evocalcet (7 switched from cinacalcet) for at least 24 months. Their mean age was 75.5 years. At baseline, cCa, phosphorus, and median intact parathyroid hormone levels were 10.76 mg/dL, 2.91 mg/dL, and 99.0 pg/mL, respectively. Osteoporosis was observed in 18 (69%), and 16 (62%) patients were on treatment for osteoporosis. Twenty-four months of evocalcet treatment significantly decreased cCa level to 9.77 mg/dL (mean change: –0.98 ± 0.91 mg/dL). Patients who switched from cinacalcet had a smaller reduction in cCa levels (–0.31 ± 0.72 mg/dL) than did those who were evocalcet-naïve (–1.23 ± 0.87 mg/dL, p = 0.019). By 24 months, 84.6% of patients had achieved a cCa level ≤10.3 mg/dL. Multivariate analysis identified baseline calcium levels as determinants of calcium level changes at 24 months. For patients not receiving osteoporosis treatment, lumbar spine BMD remained largely unchanged, whereas femoral neck BMD showed a decreasing trend. No other serious side effects requiring dose-lowering or withdrawal were noted. Evocalcet maintained its calcium-lowering effect for over 24 months in patients with PHPT, suggesting its potential as a medical treatment for surgery-ineligible patients. Careful monitoring of BMD is necessary during long-term evocalcet treatment to prevent worsening of osteoporosis.

Hailey–Hailey disease (HHD), or familial benign chronic pemphigus, is a rare autosomal dominant disorder characterized by recurrent vesicles and erosions in intertriginous areas. Topical corticosteroids are the primary treatment, but their potential systemic side effects are often overlooked. Prolonged use on compromised skin can lead to excessive absorption, increasing the risk of iatrogenic Cushing’s syndrome and adrenal insufficiency. Here, we report the case of a 50-year-old woman with HHD who had been using topical clobetasol or betamethasone for over 10 years, reaching doses up to 50 g/day. She developed Cushingoid features, metabolic abnormalities, and suppression of the hypothalamic–pituitary–adrenal (HPA) axis. After tapering off topical corticosteroids, she developed adrenal insufficiency and associated withdrawal symptoms. Following the initiation of hydrocortisone replacement therapy, psychiatric symptoms, impaired glucose tolerance, and osteoporotic fractures emerged, suggesting exacerbation of iatrogenic Cushing’s syndrome. This case highlights the risk of systemic complications from chronic topical corticosteroid use, particularly in high-absorption areas. Gradual dose reduction, close endocrine monitoring, and individualized tapering strategies are essential to prevent severe outcomes. Clinicians should be aware of potential adrenal suppression and consider endocrine evaluation in patients receiving prolonged, high-dose topical corticosteroid therapy.

In the liver, hepatocyte death occurs during the regeneration process following injury. While hepatocyte death triggers regeneration through hepatocyte proliferation in the non-steatotic liver, it impairs this process in the steatotic liver. Both the number and mode of hepatocyte death during regeneration change in the steatotic liver, affecting regeneration and thereby contributing to the progression of acute liver injury and metabolic dysfunction-associated steatotic liver disease (MASLD). Apoptosis, a non-inflammatory mode of cell death, predominantly occurs during liver regeneration. As hepatic steatosis progresses, sporadic and scattered apoptotic cell death increases, leading to delayed regeneration. In severe steatotic livers undergoing regeneration, the mode of cell death shifts to pro-inflammatory necroptosis. This transition leads to inflammation around the dead hepatocytes, resulting in zonal hepatocyte death and further impairing regeneration, thus exacerbating acute liver injury and MASLD. The integrated stress response (ISR), mediated by phosphorylation of the α-subunit of eukaryotic initiation factor 2 (eIF2α), plays a crucial role in regulating hepatocyte death during steatotic liver regeneration. The ISR-induced transcription factor C/EBP homologous protein (CHOP) promotes apoptosis, thereby delaying regeneration. When ISR is further enhanced, activating transcription factor 3 (ATF3) is upregulated, inducing the expression of receptor-interacting protein kinase 3 (RIPK3), which shifts cell death mode from apoptosis to necroptosis. While treatments for MASLD targeting apoptosis have shown limited success, future therapies targeting necroptosis and its regulatory molecules may provide novel therapeutic strategies.

Skeletal muscle is considered an endocrine and paracrine organ that has metabolic effects, and several studies have shown a positive association between muscle mass and insulin sensitivity. However, results on the relationship between muscle mass and metabolic syndrome in children and adolescents remain inconsistent. Body composition consists primarily of lean and fat mass, with lean mass being closely associated with body size. Since muscle constitutes a part of lean mass, the contribution of muscularity can be evaluated more accurately by assessing lean mass relative to fat mass, which is inversely associated with body size. This study utilized nationally representative data to assess the association between lean mass (measured via dual-energy X-ray absorptiometry) and the risk of metabolic syndrome. Model 1 was adjusted for age, sex, physical activity, alcohol consumption, smoking status, household income, and rural residence. Model 2 was based on Model 1 and the fat mass index. The odds ratio of lean mass was 1.6 (95% CI 1.4–1.8) and 2.0 (95% CI 1.8–2.3) in Model 2 and Model 1, respectively. However, the lean-to-fat mass ratio showed a strong inverse association with metabolic syndrome (adjusted odds ratio 0.2 [95% CI 0.1–0.3]), suggesting a protective effect of a greater proportion of lean mass relative to fat mass. These findings suggest that the balance of body composition plays an important role in metabolic risk. Both lean mass and fat mass need to be considered when evaluating metabolic risk in children and adolescents.

This review summarizes recent basic and clinical advances in cortisol-producing adrenal tumors, including Cushing’s syndrome (CS) and mild autonomous cortisol secretion (MACS). Recent clinical reports on the epidemiology and diagnostic challenges of CS and MACS are presented. The review highlights recent progress in understanding the molecular pathogenesis of adrenal cortisol-producing tumors. A major recent finding is the discovery of loss-of-function mutation in KDM1A as the underlying cause of the long-standing mystery of diet-dependent CS in primary bilateral macronodular adrenal hyperplasia (PBMAH). Furthermore, the recent clarification of the molecular basis of cortisol-producing adenomas (CPAs) has deepened our understanding of the functional differences in the autonomicity of CPAs between overt CS and MACS. These findings made us reconsider the categorization of adrenal tumors, including non-functioning adrenal tumors (NFATs). Finally, we reviewed the rarely discussed but critical condition of immune reconstitution inflammatory syndrome (IRIS) following CS treatment, including a case from our own experience. IRIS should be kept in mind when initiating treatment for CS patients with extremely high serum cortisol levels.

Prader–Willi syndrome (PWS) is associated with increased mortality, primarily due to complications from hyperphagia-associated obesity. Clinical trials investigating anti-hyperphagic medications are currently underway. The Hyperphagia Questionnaire for Clinical Trials (HQ-CT) is designed to assess hyperphagia in PWS, with scores ranging from 0 to 36, where higher scores indicate greater severity. However, HQ-CT scores have not yet been evaluated in Japan. Therefore, we conducted a questionnaire-based survey among patient association members. Of 605 members, the score was available in 266. Their median age was 13 years (range: 0–48). Of these, 160 were children (<18 years), and 106 were adults (≥18 years). Obesity was observed in 11% and 40% of the pediatric and adult participants, respectively. The genetic subtypes included deletions (56%) and uniparental disomies (26%). The median HQ-CT score was 5 (range: 0–30), with no significant differences observed by sex or genetic subtype. The adult participants had significantly higher scores than pediatric participants (8 vs. 4). The HQ-CT score was lower than that reported in studies conducted overseas. Among adult participants, the score was significantly higher in obese individuals than in non-obese individuals, and multivariate analysis demonstrated a positive association between the score and body mass index, after adjusting for age, sex, genotype, and growth hormone treatment during childhood (β = 0.38, p = 0.0001). However, no such association was observed in pediatric participants. These findings provide valuable insights into the hyperphagic status of PWS in Japan and implicate that hyperphagia imposes a disease burden, particularly during adulthood.

A 46-year-old man with a family history of multiple endocrine neoplasia type 1 (MEN1) presented with recurrent hypoglycemic episodes and was referred to our hospital. Based on hypoglycemia, endogenous hyperinsulinemia, and imaging findings revealing masses in the head, body, and tail of the pancreas, insulin-producing neuroendocrine neoplasms (NENs) or insulinomas were strongly suspected. A selective arterial calcium stimulation test supported this diagnosis. Additional biochemical and imaging studies suggested the presence of normocalcemic primary hyperparathyroidism (PHPT), a thymic NEN, and a prolactinoma. The patient subsequently underwent distal pancreatectomy for the pancreatic body and tail masses, enucleation of the pancreatic head mass, extended thymectomy, and subtotal parathyroidectomy. Histopathological evaluation confirmed the diagnoses of insulinoma, thymic NEN, and normocalcemic PHPT. He continued medical treatment with the dopamine receptor agonist cabergoline for the prolactinoma. Genetic testing revealed a novel heterozygous likely pathogenic frameshift MEN1 variant, c.1078del (p.Ile360Serfs*8). Based on a previous study, this variant (located within the JunD-interacting domain of the transcript Menin) has been proposed to impair the repression of JunD-mediated transcription and may contribute to aggressive tumors such as thymic NENs, which have high recurrence rates, metastatic potential, and high mortality risk. Although the specific pathological significance of this variant in tumorigenesis remains unclear, this case suggests a need for increased awareness and cautious surveillance of aggressive manifestations, including thymic lesions, in individuals harboring this variant.

This study aimed to clarify the expression levels of autophagy-related molecules, such as β-catenin, LC3B, and p62, in thyroid carcinoma (TC) cases of different histological types and clinicopathological characteristics. A total of 70 surgically resected thyroid nodules, including 43 papillary thyroid carcinoma (PTC), and other control groups such as five follicular adenoma (FA), five hyalinizing trabecular tumor (HTT), five follicular TC (FTC), six poorly differentiated TC (PDTC), and six anaplastic follicular cell-derived thyroid carcinoma (ATC), were analyzed by dual-color immunofluorescence for β-catenin, LC3B, and p62. Statistical analyses were used to determine the association of autophagy-related molecules with BRAF^V600E/TERT promoter mutations, Ki-67 labeling index, and clinicopathological characteristics. p62 immunoreactivity was most frequently observed in PTC, particularly in classical and tall cell subtypes. This protein appeared to co-localize with LC3B and β-catenin in intranuclear cytoplasmic inclusions (INIs) of PTC. Conversely, p62 expression was rarely observed in either FTC or PDTC. The expression levels of p62 and its co-localization with β-catenin and LC3B correlated significantly with the presence of the BRAF^V600E mutation. Frequent co-localization of dot-shaped perinuclear β-catenin signals with a component of the trans-Golgi apparatus in tall cell PTC subtype was also observed. This study revealed differences in the expression patterns of β-catenin, LC3B, and p62 among different TC types. Abnormal β-catenin expression may be linked to autophagy dysfunction, which triggers genomic instability and promotes tumor aggressiveness. These autophagy-related molecules may be cooperatively associated with INI formation during PTC carcinogenesis.

Prior to 1956, Graves’ hyperthyroidism was thought to be due to high levels of TSH but in that year Adams & Purves demonstrated the presence of a thyroid stimulator in Graves’ sera with a prolonged time course of action (long-acting thyroid stimulator, LATS) quite distinct from TSH. LATS was only present in the serum IgG fraction suggesting it was a thyroid stimulating autoantibody. In 1974 Graves’ IgG was shown to compete with ¹²⁵I-labelled TSH for the TSH receptor providing good evidence that Graves’ hyperthyroidism was caused by TSH receptor autoantibodies. Further breakthroughs occurred in 1989 (TSHR cloning) and 2003 (monoclonal thyroid stimulating autoantibody M22^TM). Subsequently atomic level detail of how TSHR stimulating (2007) and blocking (2011) autoantibodies interact with the TSHR became available. Cryo-EM studies followed (2022–2025) and provide a detailed understanding of how TSHR autoantibodies with different properties function. The human monoclonal autoantibody K1-70^TM with powerful TSH receptor blocking activity is now in clinical trials. It has the expected beneficial effects on Graves’ hyperthyroidism and Graves’ ophthalmopathy and is an exciting new TSHR specific drug.

To understand the mechanisms of food intake reduction after metabolic bariatric surgery, we investigated the potential antiobesity effects of undigested proteins delivered to the small intestine using enteric capsules. We utilized EUDRAGIT-coated capsules (enteric capsules) to deliver contents not into the stomach but into the small intestine. Wild-type mice were administered various proteins (soy, pea, chicken, or whey) in the enteric capsules, and the amount of food intake and weight gain by the high-fat diet were evaluated. Protein aggregation by heat treatment and vagal nerve ablation by capsaicin treatment were conducted to determine whether they affect food intake. We found that: (1) Single administration of less than 4 milligrams of soy protein in enteric capsules significantly reduced food intake. Similar effects were observed with other proteins. (2) Heat treatment increased the food intake reduction effect of whey protein with increasing levels of the enteric hormone PYY. Vagal nerve ablation by capsaicin abolished the effects of such food intake reduction. (3) Multiple administrations of soy protein in enteric capsules reduced body weight gain and liver triglyceride accumulation under high-fat diet conditions. We concluded that proteins delivered to the small intestine via enteric capsules reduced food intake and inhibited high-fat diet-induced weight gain in mice. The aggregation of protein and the capsaicin-sensitive vagal afferent nerve might play a role in this effect.

Hypophysitis is an extremely rare inflammatory condition in children that affects the pituitary gland and infundibulum. Immunoglobulin G4-related hypophysitis (IgG4-RH) is an IgG4-related disease (IgG4-RD) typified by the infiltration of IgG4-positive plasma cells into the pituitary gland, leading to fibrosis and damage. Although IgG4-RD was recently recognized as a defined clinical entity, pediatric cases of IgG4-RD are extremely rare. This report describes a histologically confirmed case of IgG4-RH in a 13-year-old girl. The patient became anorectic after several months of nonspecific symptoms such as headache and fatigue. Detailed examinations, including brain computed tomography (CT), did not detect any causes. However, repeated brain CT revealed pituitary enlargement. Further investigations identified an elevated serum IgG4 level (234 mg/dL, normal range: <118 mg/dL). Pituitary biopsy revealed increased IgG4-positive plasma cell counts in the anterior pituitary gland, fulfilling the diagnostic criteria for IgG4-RH. Steroid treatment dramatically improved her symptoms and reversed pituitary enlargement. A literature review identified 128 pediatric cases of IgG4-RD but only seven cases of pediatric IgG4-RH including our case. Although ophthalmic disease was the most common manifestation, broad clinical presentations were observed, even in pediatric cases. A slight female predominance was suggested in pediatric populations with IgG4-RD, whereas a male predominance was reported in adults. Pediatricians should consider IgG4-RH in the differential diagnosis when encountering patients with nonspecific symptoms because early diagnosis could improve the prognosis of pituitary function. Consequently, necessitating the diseases awareness.

Adrenal hormones are essential for maintaining physiological homeostasis; however, imbalances in their production can significantly impact bone metabolism. This review examines how adrenal hormone dysregulation affects bone health, focusing on the following three key pathological conditions: autonomous cortisol secretion, primary aldosteronism, and pheochromocytoma/paraganglioma. Each disorder exerts distinct effects on bone metabolism, contributing to reduced bone mass, deteriorated bone quality, and increased fracture risk. Recent advances in steroid profiling and single-cell transcriptome analysis have revealed that, in adrenocortical adenomas—such as cortisol-producing and aldosterone-producing adenomas—multiple steroid hormones contribute to these effects rather than a single hormone. Additionally, age-related changes in steroid hormones, particularly the progressive decline in dehydroepiandrosterone sulfate production and alterations in cortisol circadian rhythm, may contribute to age-associated bone fragility. This review summarizes the effects of adrenal hormone imbalances on bone metabolism in both pathological conditions and aging, which may contribute to understanding adrenal-related osteoporosis.

Individuals with the 46,XY karyotype and 17 alpha-hydroxylase/17,20 lyase deficiency (17OHD) may develop disorders/differences of sex development (DSD) accompanied by delayed puberty or primary amenorrhea. Glucocorticoid replacement is required to normalize hypertension in 17OHD, which highlights the importance of appropriate diagnostics for the selection of relevant treatment. A 16-year-old female with primary amenorrhea was found to have the 46,XY karyotype. Since the patient had spontaneous breast development, she was initially diagnosed with complete androgen insensitivity syndrome (CAIS). However, CAIS was subsequently ruled out due to an extremely low testosterone level, and 17OHD was suspected because of hypertension with low plasma renin activity, an elevated adrenocorticotropic hormone (ACTH) level, and decreased cortisol level. Two variants in CYP17A1, which were previously reported to be pathogenic, were detected and eventually confirmed the diagnosis of 17OHD. We reviewed 198 reported cases of 46,XY with 17OHD, and found spontaneous breast development in 9 of 129 (7.0%) individuals with typical female external genitalia. Although gonadal hormone production is impaired in 17OHD, 17OHD needs to be considered in differential diagnostics of 46,XY DSD even with spontaneous breast development.

Comparative endocrinology is a research subfield in endocrinology that delves into deeper understanding of the endocrine system from an evolutionary or phylogenetic perspective. To date, this approach has contributed significantly to the development of endocrinology by elucidating the evolutionary history of hormone molecules and their functions from invertebrates to vertebrates. In this review, the author initially introduces how the comparative approach has expanded and enlightened the view in endocrinology using the concept of hormones as an example. The expansion of the hormone concept blurs boundaries between signaling molecules of the three homeostatic systems, namely, the endocrine, nervous, and immune systems. Subsequently, the evolutionary history of the endocrine system is introduced in terms of both molecules and functions using the insulin superfamily as a model. This hormone family is one of the most ancient hormonal systems in animal (metazoan) phylogeny and the homologous hormones are identified in the most ancient metazoans such as sponges and hydra. In addition, this hormonal system was chosen as a topic of this review, because insulin is one of the most focused research topics in modern medicine in relation to insulin resistance and metabolic syndrome. Finally, the ancestral molecule of the insulin superfamily and its original or essential function will be discussed with some speculations to illustrate the value and joy of comparative studies that can create an original concept of the endocrine system from the evolutionary viewpoint. The comparative approach certainly helps deeper understanding of the insulin superfamily of humans.

Adult-onset hypothyroidism has long been recognized as a reversible cause of cognitive impairment. However, recent studies have shown that it is associated with structural brain alterations besides functional alterations, particularly in the hippocampus and prefrontal cortex. Neurophysiological and molecular studies have demonstrated that hypothyroidism impairs synaptic plasticity, disrupts neurotransmitter signaling, and promotes neuroinflammation, leading to learning and memory impairments. The condition also affects adult neurogenesis, particularly in the hippocampal dentate gyrus. Moreover, hypothyroidism has been linked to psychiatric disorders, including depression and anxiety, through its influence on the plasticity of the amygdala. In addition, adult-onset hypothyroidism contributes to cerebellar ataxia and peripheral neuropathy, impacting motor coordination and sensory processing. Since we come to know that adult-onset hypothyroidism in part causes irreversible changes in brain structure, prompt treatment is crucial. Furthermore, in addition to thyroid field, recent studies suggest a potential of thyroid hormone treatment beyond the thyroid disorders, such as neurodegenerative and cognitive/psychiatric disorders. This review highlights the critical role of THs in maintaining neural function and explores their therapeutic potential in addressing neurological and psychiatric conditions.