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.

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.

Somatrogon is a long-acting recombinant human growth hormone approved in several countries, including Japan, for the treatment of children with growth hormone deficiency (GHD). In this study (Clinicaltrials.gov:NCT03874013) Japanese patients with GHD initially received once-weekly somatrogon or once-daily somatropin (0.175 mg/kg/week) for 12 months in the main study period; those who completed the main study were eligible to enroll in a single-arm, 3-year open-label extension (OLE) and receive once-weekly somatrogon (0.66 mg/kg/week). The primary endpoints of the OLE included annualized height velocity (HV), change in height standard deviation score (SDS), and safety. Of 43 patients who completed the main study, 42 continued into the OLE and 40 completed the OLE. Patients were analyzed by treatment received (somatrogon vs. somatropin) during the main study. Mean (SD) HV at OLE baseline was higher in patients originally randomized to somatrogon vs. somatropin (9.78 [1.59] vs. 7.70 [1.10] cm/year); mean HV was similar between original treatment groups for all other OLE timepoints. Mean height SDS increased from main study baseline through the end of the OLE in both treatment groups. During the OLE, 22 (100%) somatrogon-treated patients and 18 (90%) somatropin-treated patients reported treatment-emergent adverse events (TEAEs). Most TEAEs were mild or moderate in severity and no patients discontinued from the OLE or required dose reductions due to TEAEs. Up to 4 years of treatment with once-weekly somatrogon resulted in improved growth response and was well tolerated in Japanese patients with pediatric GHD, including patients who switched to somatrogon from once-daily somatropin.

Clinialtrials.gov:NCT03874013

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.

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.

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.

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.

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.

Osilodrostat is an oral steroidogenesis inhibitor used in the treatment of hypercortisolism. It works by inhibiting 11-beta-hydroxylase, a key enzyme in cortisol synthesis. As a consequence of drug action, adrenal insufficiency can be observed in about 40% of patients. Although this effect has been accepted as a consequence of therapy, recent reports suggest adrenal insufficiency can persist even after discontinuation of osilodrostat. We present the case of a 74-year-old female patient who developed prolonged adrenal insufficiency after withdrawal of osilodrostat. The patient was diagnosed with ectopic ACTH-dependent Cushing’s syndrome and underwent radiotherapy for a primary lesion located in the anterior mediastinum. During treatment, osilodrostat was introduced (2 to 4 mg/d), and adrenal insufficiency developed within four weeks. Hydrocortisone (intermittently dexamethasone) replacement therapy was initiated, and over time, undetectable morning cortisol levels continued. After de-escalating the osilodrostat dose, the drug was withdrawn 15 months after initiation. Despite being off the drug for 11 months, the patient with adrenal insufficiency (morning serum cortisol: 37.2 nmol/L), still requires hydrocortisone substitution. The underlying mechanism of prolonged adrenal insufficiency after osilodrostat discontinuation remains unclear. It is unknown whether this is due to permanent inhibition of 11-beta-hydroxylase or interference at another step in steroidogenesis. Factors such as treatment duration, dose, or individual sensitivity may play a role, but other mechanisms, such as an adrenolytic effect, should also be considered. We expect an increase of similar cases, which we believe will lead to further research to better understand the mechanisms behind prolonged adrenocortical blockade after osilodrostat discontinuation.

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.

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.

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.

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.