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Thyrotoxicosis and sodium-glucose transport protein 2 inhibitors (SGLT2is) are associated with the induction of euglycemic diabetic ketoacidosis (euDKA). We herein report two cases of euDKA in patients with diabetes mellitus wherein both thyrotoxicosis and SGLT2i treatment were the underlying causes. One patient developed thyrotoxicosis during the course of type 2 diabetes mellitus, whereas the other patient was suspected of developing slowly progressive insulin-dependent diabetes mellitus during the course of Graves' disease. Although such cases are rare, there is some concern that similar cases may occur because of the increased frequency of SGLT2i use in recent years.

Context Although elevated parathyroid hormone (PTH) levels are associated with higher mortality risks, the evidence is limited as to when PTH is expected to be elevated and thus should be measured among the general population. Objective This work aimed to build a machine learning–based prediction model of elevated PTH levels based on demographic, lifestyle, and biochemical data among US adults. Methods This population-based study included adults aged 20 years or older with a measurement of serum intact PTH from the National Health and Nutrition Examination Survey (NHANES) 2003 to 2006. We used the NHANES 2003 to 2004 cohort (n = 4096) to train 6 machine-learning prediction models (logistic regression with and without splines, lasso regression, random forest, gradient-boosting machines [GBMs], and SuperLearner). Then, we used the NHANES 2005 to 2006 cohort (n = 4112) to evaluate the model performance including area under the receiver operating characteristic curve (AUC). Results Of 8208 US adults, 753 (9.2%) showed PTH greater than 74 pg/mL. Across 6 algorithms, the highest AUC was observed among random forest (AUC [95% CI] = 0.79 [0.76-0.81]), GBM (AUC [95% CI] = 0.78 [0.75-0.81]), and SuperLearner (AUC [95% CI] = 0.79 [0.76-0.81]). The AUC improved from 0.69 to 0.77 when we added cubic splines for the estimated glomerular filtration rate (eGFR) in the logistic regression models. Logistic regression models with splines showed the best calibration performance (calibration slope [95% CI] = 0.96 [0.86-1.06]), while other algorithms were less calibrated. Among all covariates included, eGFR was the most important predictor of the random forest model and GBM. Conclusion In this nationally representative data in the United States, we developed a prediction model that potentially helps us to make accurate and early detection of elevated PTH in general clinical practice. Future studies are warranted to assess whether this prediction tool for elevated PTH would improve adverse health outcomes.

Tumor-induced osteomalacia (TIO) is an acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemic osteomalacia caused by phosphaturic mesenchymal tumors (PMTs) developed in the bone or soft tissue. Diagnostic delay should be addressed, and ideal techniques to localize PMTs and efficient treatment options should be explored to improve the outcomes of this rare disease. To clarify the detailed clinical course and outcomes of TIO patients, retrospective questionnaire surveys were conducted among physicians from the Japanese Society for Bone and Mineral Research (JSBMR) and the Japan Endocrine Society (JES). The primary survey collected the number of TIO patients between January 2007 and December 2018. The secondary survey aimed to obtain the detailed characteristics, laboratory data, and outcomes. Eighty-eight patients (52 males, mean: 52 years old) were included, and 24 patients were clinically diagnosed with TIO without localized PMTs. The median duration from the onset to detection of high FGF23 levels was 3.4 years, with 77 patients being initially misdiagnosed. Among the methods used to detect small, localized PMTs (≤10 mm), fluorine-18-fluorodeoxyglucose-positron emission tomography/computed tomography and somatostatin receptor scintigraphy were less sensitive than somatostatin receptor positron emission tomography/computed tomography (SRPET/CT). Systemic venous sampling (SVS) of FGF23 was performed in 53 patients; among them, SVS was considered useful for detecting localized PMTs in 45 patients with diverse tumor sizes. Finally, 45 patients achieved biochemical remission by surgery, 39 patients continued pharmaceutical treatment, including burosumab (11 patients), and four patients died. These results encouraged us to further increase the awareness of TIO and to improve the accessibility of SRPET/CT and SVS. Further evidence about the efficacy of new pharmaceutical treatments is awaited. © 2022 American Society for Bone and Mineral Research (ASBMR).

Context Conventional treatment of X-linked hypophosphatemia (XLH) was reported to prevent dental complications, but whether the preventive effect was different among different types of teeth, including anterior teeth and molar teeth, is uncertain. Evidence of the preventive effect of conventional treatment on ectopic ossifications is also limited. Objective To compare dental complications and ectopic ossifications among adults with XLH with early ( Methods This retrospective observational study included a total of 30 adults with XLH; orthopantomograms, spinal computed tomography scans, and X-rays of hip/knee joints were studied. Dental complications, including the decayed, missing, filled (DMF) index and devitalized teeth, apical periodontitis, and periodontitis, were evaluated. The ossification of the anterior/posterior longitudinal ligament and yellow ligament indexes (OA/OP/OY indexes) and the sum of the OA/OP/OY indexes (OS index) were utilized to evaluate the severity of spinal ligament ossification. The severity of the hip/knee osteophytes was evaluated using the Kellgren–Lawrence (KL) classification. Results The number of sound teeth was significantly lower and the DMF index was significantly higher in patients with late treatment. The severity of dental complications in the anterior tooth and molar tooth, OA/OP/OY/OS index, and KL grade were not significantly different among patients with early treatment and those with late treatment. Conclusion Early treatment could prevent dental complications but did not prevent ectopic ossification in adult patients with XLH. The difference in the preventive effect was not observed among different types of teeth.

Context Tumor-induced osteomalacia (TIO) is one of the most common forms of acquired fibroblast growth factor 23 (FGF23)-related hypophosphatemia and is usually caused by phosphaturic mesenchymal tumors (PMTs). Although the complete resection of PMTs can cure TIO, preoperative localization of tumors by standard imaging modalities is often challenging. In addition to 18F-fluoro-2-deoxy-D-glucose positron emission tomography–computed tomography (FDG-PET) and 111In-pentetreotide scintigraphy (SRS), systemic FGF23 venous sampling (FGF23VS) has been used to help localize PMTs in specialized institutions. Objective This study aimed to evaluate the diagnostic performance of each imaging test and their combinations in localizing PMTs. Methods In an observational retrospective study of patients with adult-onset FGF23-related osteomalacia who underwent all 3 imaging studies (FDG-PET, SRS, and FGF23VS), the rate of successful preoperative localization of the tumors was evaluated only in the patients with pathological diagnoses of PMTs, considering the possibility that pathogenesis of patients without identified tumors might be due to other causes such as late-onset hereditary FGF23-related hypophosphatemia. Results A total of 30 Japanese patients with TIO (median age, 60 years [range, 28-87 years]; 10 women [33.3%]) were included in the study. The success rate of preoperative localization for each test and combinations of 2 or 3 tests among 18 patients with PMTs was as follows: 72% (FDG-PET), 72% (SRS), 94% (FGF23VS), 89% (FDG-PET, SRS), 100% (FDG-PET, FGF23VS), 94% (SRS, FGF23VS), and 100% (FDG-PET, SRS, and FGF23VS). Conclusion We observed the highest localization rate of PMTs in patients with identified PMTs with the combination of FDG-PET and FGF23VS.

Homozygous ENPP1 mutations are associated with autosomal recessive hypophosphatemic rickets type 2 (ARHR2), severe ossification of the spinal ligaments, and generalized arterial calcification of infancy type 1. There are a limited number of reports on phenotypes associated with heterozygous ENPP1 mutations. Here, we report a series of three probands and their families with heterozygous and compound heterozygous ENPP1 mutations. The first case (case 1) was a 47-year-old male, diagnosed with early-onset osteoporosis and low-normal serum phosphate levels, which invoked suspicion for hypophosphatemic rickets. The second and third cases were 77- and 54-year-old females who both presented with severe spinal ligament ossification and the presumptive diagnosis of diffuse idiopathic skeletal hyperostosis (DISH). Upon workup, fibroblast growth factor 23 (FGF23) was noted to be relatively high in case 2 and serum phosphorous was low-normal in case 3, and the diagnoses of X-linked hypophosphatemic rickets (XLH) and ARHR2 were considered. Genetic testing for genes related to congenital hypophosphatemic rickets was therefore performed, revealing heterozygous ENPP1 variants in cases 1 and 2 (case 1, c.536AG, p.Asn179Ser; case 2, c.1352AG, p.Tyr451Cys) and compound heterozygous ENPP1 variants in case 3 constituting the same variants present in cases 1 and 2 (c.536AG, p.Asn179Ser and c.1352AG, p.Tyr451Cys). Several in silico tools predicted the two variants to be pathogeneic, a finding confirmed by in vitro biochemical analysis demonstrating that the p.Asn179Ser and p.Tyr451Cys ENPP1 variants possessed a catalytic velocity of 45% and 30% compared with that of wild-type ENPP1, respectively. Both variants were therefore categorized as pathogenic loss-of-function mutations. Our findings suggest that ENPP1 mutational status should be evaluated in patients presenting with the diagnosis of idiopathic DISH, ossification of the posterior longitudinal ligament (OPLL), and early-onset osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR).

Among the side effects of methimazole (MMI) for the treatment of Graves’ disease, MMI-induced acute pancreatitis (MIP) is a rare adverse reaction, with only 7 cases being reported to date. However, 2 large-scale population-based studies recently revealed that the risk of MIP was significantly higher, ranging from 0.02% to 0.56%. Although MIP is common in middle-aged and elderly Asian women, its pathogenesis remains largely unknown. We herein present a case of a 72-year-old Japanese woman with Graves’ disease who developed MIP 12 days after the initiation of MMI. The MMI was discontinued, the patient was switched to propylthiouracil (PTU) therapy, and pancreatitis gradually resolved. Serological human leukocyte antigen (HLA) typing identified HLA-DRB1*08:03:02. This HLA allele was previously detected in a patient with MIP and is one of the major risk factors for agranulocytosis induced by antithyroid drugs, including PTU as well as MMI. In cases of MIP, PTU is being considered as an alternative to MMI; however, its safety needs further investigation and patients require close monitoring after the switch to PTU. Further studies are warranted, particularly on the relationship between MIP and the presence of HLA alleles causing antithyroid drug-induced agranulocytosis.

A 77-year-old-man with renal cell carcinoma who was undergoing nivolumab treatment visited our department due to hyperglycemia; his plasma glucose level was 379 mg/dL. Although his serum C-peptide immunoreactivity (CPR) level was preserved (5.92 ng/mL), we suspected an onset of fulminant type 1 diabetes mellitus (FT1DM) and immediately started insulin therapy. His CPR levels gradually decreased and were depleted within 1 week. We later discovered that the patient's casual CPR level had been abnormally high (11.78 ng/mL) 2 weeks before his admission. Hence, the possibility of FT1DM in hyperglycemic patients undergoing nivolumab treatment should not be excluded, even with a preserved CPR level.

Primary aldosteronism (PA) usually accompanies suppressed plasma renin activity (PRA) through a negative feedback mechanism. While some cases of PA with unsuppressed PRA were reported, there have been no studies about the characteristics of PA with unsuppressed PRA; thus, these characteristics were examined herein. Nine patients with unsuppressed PRA and 86 patients with suppressed PRA were examined. All patients underwent segmental adrenal venous sampling (sAVS) and adrenalectomy, and were pathologically confirmed to have cytochrome P450 11B2 (CYP11B2)-positive aldosterone-producing adenoma according to international histopathology consensus criteria. Unsuppressed and suppressed PRA were defined as PRA levels of > 1.0 and ≤ 1.0 ng/mL/hr, respectively, in multiple blood samples obtained in the resting position. The unsuppressed PRA group had higher morning cortisol levels (12.6 [8.5, 13.5] vs. 8.5 [7.1, 11.0] μg/dL, P = 0.03) and higher cortisol levels after a 1 mg dexamethasone suppression test (DST) (2.2 [1.6, 2.5] vs. 1.3 [1.0, 1.9] μ g/dL, P = 0.004) than the suppressed PRA group. The unsuppressed PRA group also showed higher aldosterone levels on the non-surgical side during sAVS (P = 0.02 before adrenocorticotropic hormone (ACTH) stimulation, P = 0.002 after ACTH stimulation), a higher intensity of CYP17 expression in the resected adrenal gland (P = 0.02), and a lower clinical complete success rate 1 year after surgery (P = 0.04) compared with those in the suppressed PRA group. These findings suggest that PA should not be ruled out by unsuppressed PRA among patients with hypertension, particularly when their cortisol levels remain unsuppressed in the 1 mg DST. Meanwhile, it should be acknowledged that patients with unsuppressed PRA have higher aldosterone levels on the non-surgical side, and a lower likelihood of postoperative complete clinical success is to be expected.

Pheochromocytoma (PCC) is rare catecholamine-producing endocrine tumor that metastasizes in approximately 10% of cases. As a functional imaging of PCC, 123I-metaiodobenzylguanidine (MIBG) scintigraphy was established, and some cases of PCC exhibit negative accumulation on MIBG scintigraphy, indicating a high risk of metastasis. Additionally, germline genetic variants of PCC are evident in approximately 30% of cases, although the genotype-phenotype correlation in PCC, especially the association between genetic mutations and MIBG scintigraphy, remains unclear. A 33-year-old man was admitted to our hospital for further examination for hypertension. He was diagnosed with sporadic PCC, and left adrenalectomy was performed. The adrenal tumor was negative on MIBG scintigraphy. Histology of the tumor revealed a moderately differentiated PCC. Target gene testing revealed a mutation in RET (c.2071G > A). This mutation has been reported to be a tumor-developing gene involved in the pathogenesis of PCC. Moreover, the RET mutation is the only gene mutation reported in a previous study of PCC with negative results on MIBG scintigraphy, except for the SDHB gene mutation, which is a common mutation in metastatic PCC. Correctively, the present RET gene mutation may be associated to MIBG-scintigraphy negative PCC and its pathophysiology. Clinicians should follow such cases more cautiously in clinical practice.

In primary aldosteronism (PA), it is reported that secondary hyperparathyroidism (SHPT) is caused by increased urinary Ca excretion due to excessive aldosterone, which may decrease bone mineral density and increase fracture risk. However, there have been few reports that evaluated changes in bone metabolism markers in detail before and after the treatment for PA. In this retrospective study, we evaluated changes in multiple bone metabolism markers before and after adrenalectomy. We analyzed 16 patients who underwent adrenalectomy for unilateral aldosterone-producing adenoma (APA) in our hospital from April 2009 to November 2017 and compared various bone metabolism markers before and after surgery. All patients were diagnosed with unilateral hyperaldosteronism by segmental adrenal venous sampling. Patients with bilateral hyperaldosteronism and bone disease were excluded. We compared changes in levels of serum Ca, 24-hour urinary Ca excretion (u-Ca), intact parathyroid hormone (iPTH), tartrate-resistant acid phosphatase 5b (TRACP-b5), bone-specific alkaline phosphatase (BAP), and undercarboxylated osteocalcin (ucOC) before and one year after surgery. Sixteen patients consisted of 8 males and 8 females (Mean age =49.6 years old, BMI =23.7 kg/m2, hypertension duration =10.9 years, blood pressure =135/84 mmHg, eGFR =86.6 mL/min/1.73 m2). After surgery, aldosterone hypersecretion improved markedly (plasma aldosterone (PAC); 278.4 ± 167.5 to 96.9 ± 47.1 pg/mL, urinary aldosterone; 28.6 ± 22.7 to 5.6 ± 3.9 μg/day). Significant increase in serum Ca (8.74 ± 0.24 to 9.31 ± 0.80 mg/dL, P < 0.001) and decreases in u-Ca (0.23 ± 0.10 to 0.09 ± 0.07 g/day, P = 0.002) and iPTH (86.7 ± 40.8 to 54.4 ±16.3 pg/mL, P < 0.001) were observed. In addition, significant decreases in TRACP-b5 (373.0 ± 180.1 to 211.9 ± 101.2 mU/dL, P < 0.001), BAP (16.6 ± 7.06 to 10.8 ± 3.73 μg/L, P < 0.001), and ucOC (7.56 ± 5.0 to 4.04 ± 2.3 ng/mL, P = 0.004) levels were observed. The change in iPTH had significant positive correlation with the change in PAC (r = 0.55, P = 0.026), while it had no correlation with the change in u-Ca. The correction of hyperaldosteronism by adrenalectomy decreased urinary Ca excretion, iPTH level, and bone tune over. In addition, our results suggest that the increase in iPTH was caused by hyperaldosteronism, independent from the excess in urinary calcium excretion.

Introduction: Primary aldosteronism (PA), characterized by a hypersecretion of aldosterone from the adrenal gland, increases the risks of cardiovascular disease. However, there is limited report on the changes of echocardiographic parameters after adrenalectomy in patients with PA. This study aimed to assess the multiple changes of echocardiographic parameters, including left atrial (LA) enlargement, diastolic dysfunction, left ventricular (LV) systolic function, and LV hypertrophy, pre- and post-adrenalectomy. Methods: In a retrospective cohort study, we analyzed a total of 122 patients with aldosterone-producing adenoma who underwent unilateral adrenalectomy from 2009 to 2016. All patients were diagnosed with unilateral hyperaldosteronism on the basis of segmental adrenal venous sampling (S-AVS). We excluded patients with a history of myocardial infarction, atrial fibrillation, or bilateral hyperaldosteronism. Echocardiography was performed before and 1-year after adrenalectomy and we evaluated multiple echocardiographic parameters. Results: After surgery, blood pressure, plasma aldosterone concentration and 24-hour urinary aldosterone excretion declined significantly (all P < 0.001). In echocardiography, LA diameter (LAD) decreased significantly (34.3 [30.9-37.5] to 33.8 [30.5-36.0] mm; P = 0.001). Early diastolic filling velocity to septal early diastolic mitral annular tissue velocity ratio tended to decrease (8.25 [6.99-9.58] to 7.9 [6.8-9.4], P = 0.22). LV diastolic internal dimension (48.3 [45.3-51.3] to 46.8 [42.6-49.5] mm), LV posterior wall thickness (8.5 [7.5-9.4] to 7.9 [7.4-9.0] mm), and LV mass index (LVMI) (101.17 [84.3-123.2] to 87.4 [77.0-103.2] g/m2) decreased significantly (all P < 0.001). Ejection fraction, fractional shortening, cardiac index did not change significantly. The most influencing factors to changes in LAD and LVMI were pre-operative values of each echocardiographic parameter. Conclusion: Our results indicate that correction of hyperaldosteronism by adrenalectomy improves LA enlargement and LV hypertrophy in patients with aldosterone-producing adenoma. The improvement effects on these parameters may be exerted depending on pre-operative abnormality. Adrenalectomy could be an effective treatment for decreasing risks of cardiovascular disease by improving blood pressure and cardioprotective effect.