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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.

Hypophosphatasia (HPP) is an inherited disease caused by variants of the ALPL gene encoding tissue‐nonspecific alkaline phosphatase. Adult‐onset HPP (adult HPP), known as a mild form of HPP, develops symptoms involving osteomalacia after the age of 18 years. Asfotase alfa (AA) is a modulated recombinant human alkaline phosphatase (ALP) that has been established as a first‐line therapy for severe forms of HPP, such as perinatal and infantile forms. We described a 64‐year‐old female who presented with pseudofractures in bilateral femur diaphyses and impaired mobility. Low serum ALP activity and a high concentration of urine phosphoethanolamine indicated the diagnosis of HPP, which was confirmed by the identification of a homozygous variant in the ALPL gene (c.319G > A; p.Val107Ile). An in vitro transfection experiment to measure the ALP activity of this novel variant protein was performed, resulting in 40% of the residual enzymatic activity compared with the wild type. AA was initiated to facilitate the union of pseudofracture and to improve mobility. After 6 months, radiographic images revealed the disappearance of fracture lines, and improvement of ambulatory ability was confirmed by the 6‐minute walk test (525 to 606 m). The EQ‐5D‐5L index was also improved (0.757 to 0.895). Within a follow‐up period, the levels of urine pyrophosphate corrected by urine creatinine (uPPi/Cre) declined in parallel with the level of plasma PPi (plasma PPi: 6.34 to 1.04 μM, uPPi/Cre: 226.8 to 75.4 nmol/mg). The beneficial effect of AA on pseudofracture healing in adult HPP was presented, although the application of AA should be restricted to patients exhibiting relatively severe manifestations. In addition, a novel pathogenic variant of the ALPL gene was identified with the supportive result of functional analysis. Furthermore, when monitoring patients with HPP treated with AA, uPPi/Cre might be a convenient substitute for plasma PPi, which requires immediate filtration after blood sampling. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

SummarySubtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them.PurposeThe main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age.MethodsClinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022.ResultsAmong 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides.ConclusionIf clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF.

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.

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.

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.

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.