Impact of a change to a novel chemiluminescent immunoassay for measuring plasma aldosterone on the diagnosis of primary aldosteronism.

In Japan, the standard method for measuring plasma aldosterone concentration (PAC) for primary aldosteronism (PA) diagnosis was changed from radioimmunoassay (RIA) to a novel chemiluminescent enzyme immunoassay (CLEIA). The purpose of this study is to simulate the possible impact of the change on PA diagnosis. This retrospective study assessed 2,289 PA patients. PACs measured by conventional RIA were transformed to estimated PACs (CLEIA) as follows: RIA (pg/mL) = 1.174 × CLEIA (pg/mL) + 42.3. We applied the estimated PAC (CLEIA) to the conventional cut-off of aldosterone-to-renin activity ratio ≥200 for screening and captopril challenge test (CCT) and PAC ≥60 pg/mL for saline infusion test (SIT). Application of the estimated PAC to screening and confirmatory tests decreased the number of PA diagnoses by 36% (743/2,065) on CCT and 52% (578/1,104) on SIT (discrepant cases). Among the discrepant cases, 87% (548/628) of CCT and 87% (452/522) of SIT were bilateral on adrenal venous sampling (AVS). Surgically treatable aldosterone-producing adenomas (APAs) were observed in 6% (36/579) and 5% (23/472) of discrepant cases on CCT and SIT, respectively; most were characterized by hypokalemia and/or adrenal nodule on CT imaging. Application of the PAC measured by the novel CLEIA to conventional cut-offs decreases the number of PA diagnoses. Although most discrepant cases were bilateral on AVS, there are some APA cases that were characterized by hypokalemia and/or adrenal tumor on CT. Further studies which evaluate PACs measured by both RIA and CLEIA for each patient are needed to identify new cut-offs for PAC measured by CLEIA.

An elderly patient with 17α-hydroxylase deficiency misdiagnosed as primary aldosteronism: a case report.

BACKGROUND: 17α-hydroxylase deficiency (17OHD) is a rare autosomal recessive disorder. Aldosterone levels are usually low in patients with 17OHD. However, among the approximately 150 cases of 17OHD reported to date, aldosterone levels were not low in all cases. Therefore, some 17OHD cases may have been misdiagnosed as primary aldosteronism (PA) cases. Often before puberty, 17OHD is diagnosed because of abnormal genital morphology and menstrual irregularities. However, we report a very rare case of 17OHD in an elderly patient with a high aldosterone/renin ratio (ARR) similar to that in PA. CASE PRESENTATION: A 63-year-old Japanese woman was transferred to our medical facility for the evaluation of bilateral adrenal hypertrophy, which was incidentally discovered during an abdominal examination after cholecystectomy. The patient had hypokalemia and a high aldosterone/renin ratio. Her medical history included hypertension and right intracerebral capsular hemorrhage at the age of 30 years. Additional testing revealed low cortisol, high adrenocorticotropic hormone, and low testosterone and dehydroepiandrosterone sulfate, indicating congenital adrenal hyperplasia. Genetic analysis revealed a mutation in the CYP17A1 gene and a karyotype of 46, XY; hence, she was diagnosed with 17OHD. CONCLUSION: 17OHD can resemble PA. The combination of a high ARR and low cortisol level should trigger the consideration of 17OHD.

Comparison and commutability study between standardized liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) and chemiluminescent enzyme immunoassay for aldosterone measurement in blood.

A commutability confirmation test for the blood aldosterone measurement was performed on liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) as a designated comparison method (DCM) and four chemiluminescent enzyme immunoassay (CLEIA) measurement procedures based on metrological traceability. A conventional radioimmunoassay (RIA) and two measurement procedures of CLEIA which obtains RIA equivalent values were also compared. The relationship between the DCM value and the CLEIA value with respect to 120 pg/mL of the RIA value, which is the screening criterion of primary aldosteronism (PA) was clarified. For the correlation test, 75 samples of patient serum and plasma were used. Regression analysis revealed that the standardized LC-MS/MS and four CLEIA measurement procedures were in good agreement. This is the effect of measurement specificity and calibration using by certified reference material (CRM). The median of the LC-MS/MS corresponding to 120 pg/mL of RIA was 48.5 pg/mL. In the mean of standardized four CLEIA values corresponding to the 48.5 pg/mL of LC-MS/MS value was 47.51 pg/mL and the standard deviation (SD) was 2.93 pg/mL. However, the correlation between the RIA value and the RIA equivalent of the two measurement procedures by CLEIA differed depending on the measurement procedure. This is due to the influence of RIA measurement performance. Standardized CLEIA measurements are suitable for routine measurement procedure. When converting the LC-MS/MS equivalent value by the standardized CLEIA to the conventional RIA value, it is necessary to use the conversion formula.

Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021.

Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

Predictors of renal function after adrenalectomy in patients with Cushing or subclinical Cushing syndrome.

PURPOSE: The postoperative course of renal function remains unclear in Cushing syndrome. We examined changes in renal function after adrenalectomy in patients with Cushing syndrome and attempted to identify predictors of renal impairment. METHODS: The study population comprised 76 patients who underwent adrenalectomy for Cushing and subclinical Cushing syndrome between 2001 and 2018. Renal function and other factors were evaluated pre-operation, at 1 postoperative month, and 1 postoperative year. We defined a ≥10% decrease in the estimated glomerular filtration rate at 1 postoperative year as renal impairment, and predictors associated with this reduction were investigated. The relationship between renal function and steroid replacement after surgery was also examined. RESULTS: Mean pre-operative estimated glomerular filtration rate was 82.2 ml/min/1.73 m2 . While mean estimated glomerular filtration rate was significantly lower at 1 postoperative month than the pre-operative value (71.7 ml/min/1.73 m2 [89.1%], p < 0.001), no significant differences were observed between 1 postoperative year and pre-operation (79.5 ml/min/1.73 m2 [97.6%], p = 0.108). Twenty-six patients (34.2%) developed renal impairment. A multivariate analysis identified a low pre-operative adrenocorticotropic hormone level as an independent predictor of renal impairment (odds ratio 6.30, p = 0.031). Among 43 patients with available records of steroid replacement history, 18 (41.9%) developed renal impairment. The ratio of patients with a reduced steroid replacement dose at 1 postoperative month was significantly lower among patients with renal impairment than those without (22.2% vs. 56.0%, p = 0.027). CONCLUSIONS: The pre-operative adrenocorticotropic hormone level was a predictor of renal function after adrenalectomy in patients with Cushing or subclinical Cushing syndrome.

Risk factors for haemodynamic instability and its prolongation during laparoscopic adrenalectomy for pheochromocytoma.

OBJECTIVE: Pheochromocytoma is a rare neuroendocrine tumour that secretes catecholamines and originates in the adrenal gland. Although surgical resection is the only curative therapy for pheochromocytoma, it is associated with a risk of haemodynamic instability (HDI), such as extremely high blood pressure and/or post tumour removal hypotension and shock. We investigated the risk factors for HDI during pheochromocytoma surgery. DESIGN AND PATIENTS: Eighty-two patients who underwent laparoscopic adrenalectomy for pheochromocytoma between July 2002 and February 2020 were examined. We excluded 3 patients with bilateral disease and 11 without detailed 24 h urinary data. We defined HDI as systolic blood pressure ≥ 200 or <80 mmHg. We investigated the risk factors for HDI during laparoscopic adrenalectomy for pheochromocytoma. RESULTS: There were 29 males and 39 females with a median age of 50.5 years. Tumours were localised on the right adrenal gland in 28 patients and on the left in 40. The median tumour diameter was 37.5 mm and the median pneumoperitoneum time was 93.5 min. Twenty-five out of sixty-eight patients (37%) developed HDI. A multivariate analysis identified diabetes mellitus (DM; odds ratio: 3.834; 95% confidence interval: 1.062-13.83; p = .04) as an independent predictor of HDI. In terms of hormonal data, median 24 h urinary epinephrine levels (p = .04) and metanephrine levels (p = .01) were significantly higher in the HDI group. DM was also considered as a risk factor for prolonged HDI (p = .02). CONCLUSION: Surgeons and anaesthesiologists need to be aware of the risk of HDI and its prolongation during laparoscopic adrenalectomy for pheochromocytoma for DM patients.

Appropriate timing for a biochemical evaluation after adrenalectomy for unilateral aldosterone-producing adenoma.

CONTEXT: The oversecretion of plasma aldosterone by unilateral aldosterone-producing adenoma (APA) can be cured by adrenalectomy. However, the time needed for the endocrine environment to normalize remains unclear. OBJECTIVE: To clarify adequate timing for a biochemical evaluation in unilateral APA patients after adrenalectomy. DESIGN AND PATIENTS: A total of 166 unilateral APA patients were retrospectively reviewed. We evaluated the plasma aldosterone concentration (PAC) (pg/mL), active renin concentration (ARC) (pg/mL), aldosterone-renin ratio (ARR; PAC/ARC), serum potassium concentration and estimated glomerular filtration rate (eGFR) at 1, 3 and 6 postoperation months (POM). RESULTS: PAC was significantly lower at 1POM than at presurgery (presurgery; 407.2, 1 POM; 90.0 pg/mL, P < .001). ARC did not increase from baseline at 1POM, but significantly increased at 3POM (presurgery; 4.43, 1POM; 4.87, 3POM; 11.3 pg/mL, P < .001). ARR significantly decreased at 1POM (presurgery; 146.9, 1 POM; 26.3, P < .001) although ARC did not increase at 1POM. Among the 34 patients who had hypokalaemia presurgery, it was resolved in 28 (82%) at 1POM and in all (100%) at 3POM. The biochemical outcomes at 1POM were 131 (79%) complete, 20 (12%) partial and 15 (9%) absent successes, while at 3POM, 147 (89%) were complete, 9 (5%) partial and 10 (6%) absent. Twenty-three (14%) patients were reclassified into different biochemical outcomes between 1 and 3POM, whereas only 5 (3%) changed between 3 and 6POM. CONCLUSION: The appropriate timing for a biochemical evaluation of unilateral APA patients treated with laparoscopic adrenalectomy appears to be 3 months or more after surgery.

Obesity predicts persistence of resistant hypertension after surgery in patients with primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) is considered a major cause of resistant hypertension (RHT). The prevalence of RHT has been recently reported to reach 18% in general hypertension. However, little is known about the prevalence and the outcomes after adrenalectomy of RHT in PA. Therefore, we aimed to clarify the prevalence and surgical outcomes in patients with both PA and RHT. PATIENTS AND DESIGN: Among 550 patients who underwent adrenalectomy for unilateral PA in the Japan PA Study, RHT was defined as an uncontrolled blood pressure (≥140/90 mm Hg) despite treatment with at least any three antihypertensives or hypertension controlled with at least four drugs. Surgical outcome was assessed by the biochemical and clinical outcome. RESULTS: Although 40 (7.3%) patients fulfilled the criteria for preoperative RHT, this should be underestimated because only 36% of patients with postoperative RHT were classified as having preoperative RHT. The prevalence of preoperative RHT was approximately 20% when estimated using the total number of patients with postoperative RHT and the ratio of postoperative RHT in patients with preoperative RHT. Although an improvement in hypertension was achieved in approximately 80% of patients with preoperative RHT, 20% of these exhibited persistent RHT. These patients were more obese than those for whom RHT improved after surgery. Notably, body mass index of ≥25 kg/m2 was an independent predictor of postoperative RHT. CONCLUSIONS: The prevalence of RHT in PA was lower than expected even with the adjustment for underestimation. Furthermore, obesity is an independent factor predicting the postoperative persistence of RHT.

Effect of long-term amiodarone treatment on thyroid function in euthyroid Japanese patients: a 12-month retrospective analysis.

Amiodarone is an effective antiarrhythmic drug. However, it is associated with changes in thyroid function in euthyroid patients due to its high iodine content and intrinsic drug effects. Studies have been conducted in iodine-deficient and iodine-sufficient countries; however, data from countries with excessive iodine intake are lacking. Thus, this study aimed to evaluate the effect of long-term amiodarone treatment on thyroid function in euthyroid Japanese patients. Japanese adults aged ≥18 years who were treated with amiodarone for at least 90 consecutive days were included in this retrospective chart review. Patients with abnormal thyroid function test results at baseline were excluded. Serial changes in thyroid function tests at baseline and at days 30, 90, 180, 270, and 360 were analyzed using a mixed-effects model for repeated measures. In total, 46 patients with a mean age of 63.7 years were evaluated. The mean TSH level significantly increased from 1.62 µIU/mL at baseline to 3.43, 2.75, 2.84, 2.78, and 2.65 µIU/mL at days 30, 90, 180, 270, and 360, respectively. The mean free T4 level significantly increased from 1.3 ng/dL at baseline to 1.4, 1.5, 1.5, 1.5, and 1.5 ng/dL at days 30, 90, 180, 270, and 360, respectively. The mean free T3 level significantly decreased from 2.8 pg/mL at baseline to 2.4, 2.3, 2.3, 2.4, and 2.4 pg/mL at days 30, 90, 180, 270, and 360, respectively. In conclusion, significant changes in thyroid function persisted not only in the acute phase but also in the chronic phase of long-term amiodarone treatment.

Usefulness of the index calculated as the product of levels of fasting plasma glucose and hemoglobin A1c for insulinoma screening.

Hypoglycemia is the major symptom of insulinoma. Chronic and recurrent hypoglycemia leads to the disappearance of autonomic symptoms and persistence of non-specific symptoms alone, possibly contributing to the delayed diagnosis of insulinoma and accounting for several undiagnosed cases. We previously reported the usefulness of hemoglobin A1c (HbA1c) and glycated albumin as markers for early insulinoma screening; however, their diagnostic prediction performance and diagnostic performance were not satisfactory. We hypothesized that the product of fasting plasma glucose (FPG) and HbA1c levels (FPG × HbA1c index) is low in insulinoma, and this index may be a useful marker for screening. This cross-sectional multicenter study compared 82 insulinoma patients with 100 age-, sex-, and body mass index-matched controls with normal glucose tolerance based on 75-g oral glucose tolerance test. The FPG × HbA1c index was significantly lower in the insulinoma group than in the control group. Receiver operating curve analysis showed that the optimal cutoff point of the FPG × HbA1c index to diagnose insulinoma was 447.1, and the area under the curves (AUCs) of the FPG × HbA1c index and HbA1c were 0.998 and 0.966, respectively. The AUC of the index was significantly higher than that of HbA1c (p = 0.010). Conversely, no significant difference existed between the AUC of the FPG × HbA1c index and that of the FPG/fasting immunoreactive insulin index. Thus, in apparently healthy population, the product of FPG and HbA1c yields a useful index for insulinoma screening in terms of accuracy and versatility.

Umbilical closure using 2-octyl cyanoacrylate in transumbilical laparoscopic adrenalectomy: A randomized controlled trial.

OBJECTIVES: To evaluate postoperative pain and esthetic outcomes in patients undergoing transumbilical laparoscopic adrenalectomy with wound closure using 2-octyl cyanoacrylate. METHODS: A total of 26 patients who underwent laparoscopic adrenalectomy with the transumbilical approach and agreed to participate in this study were included. Patients were randomly divided into two groups: the 2-octyl cyanoacrylate group (Glue group) or the non-use group (non-Glue group). A single surgeon (AM) carried out all procedures between 2014 and 2017. RESULTS: There were no significant differences in the clinical background of the Glue and non-Glue groups. The number of patients with moderate or high levels of pain in the resting/moving period on postoperative days 1, 2 and 3 was 6/10 (46%/77%), 6/9 (46%/69%) and 3/5 (23%/38%) in the non-Glue group, and 5/7 (38%/54%), 2/7 (15%/54%) and 1/3 (8%/23%) in the Glue group. These differences were not significant. In the subgroup analysis of patients aged <50 years, the numbers were 4/6 (57%/86%), 5/7 (71%/100%) and 3/5 (43%/71%) in the non-Glue group, and 3/4 (33%/44%), 1/4 (11%/44%) and 0/1 (0%/11%) in the Glue group in the resting/moving period. On postoperative days 2 and 3, these differences were significant (P = 0.035 and 0.037 in the resting period, and P = 0.017 and 0.013 in the moving period). CONCLUSIONS: 2-octyl cyanoacrylate can be used safely for laparoscopic adrenalectomy with the transumbilical approach, and might be useful for reducing postoperative pain in patients aged <50 years.

Usefulness of hemoglobin A1c and glycated albumin measurements for insulinoma screening: an observational case-control study.

BACKGROUND: Insulinoma represents hypoglycemia as a predominant symptom; the autonomic symptoms may be resolved by chronically recurrent hypoglycemia resulting in the persistence of non-specific symptoms alone. Therefore, it has been estimated that there are many patients in whom the disease takes longer to diagnose and has remained undiagnosed. Although some parameters exist for the definitive diagnosis of the disease, there are currently no indices for early screening. Indices of glycemic control, hemoglobin A1c (HbA1c), and glycated albumin (GA) may be useful for the screening of patients with insulinoma having chronic hypoglycemia because the values become low in such a condition. Because there are no articles that have reported the point, we examine the effective cutoff values of HbA1c and GA for the diagnosis of insulinoma in the present study. METHODS: In a multicenter cross-sectional study, 31 patients with insulinoma were included for comparison with 120 control subjects with normal glucose tolerance based on 75 g oral glucose tolerance tests whose characteristics were matched to the patients. The primary outcomes were optimal cutoff values of HbA1c and GA for the screening of insulinoma. RESULTS: HbA1c was significantly lower in the insulinoma group at 4.7 ± 0.4% compared to the healthy control group at 5.7 ± 0.3% (p < 0.001), and GA was significantly lower in the insulinoma group at 11.6 ± 1.8% compared to the healthy control group at 14.5 ± 1.0% (p < 0.001). According to a receiver operating characteristic (ROC) analysis, optimal cutoff values of HbA1c and GA for the diagnosis of insulinoma were 5.0 and 12.4%, respectively. Area under the curve values of HbA1c and GA were 0.970 and 0.929, respectively, showing no significant difference (p = 0.399). CONCLUSIONS: In the present study, HbA1c and GA values in patients with insulinoma were significantly lower compared to the healthy controls, and effective cutoff values for screening were shown in the diagnosis of insulinoma for the first time. HbA1c and GA can be useful indices for insulinoma screening. Because malignant insulinoma have a similar diagnostic process to that of benign insulinoma, these could be useful for malignant insulinoma.

Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism.

CONTEXT: The current Endocrine Society Guideline suggests that patients aged <35 years with marked primary aldosteronism (PA) and unilateral adrenal lesions on adrenal computed tomography (CT) scan may not need adrenal vein sampling (AVS) before proceeding to unilateral adrenalectomy. This suggestion is, however, based on the data from only one report in the literature. OBJECTIVE: We sought to determine the accuracy of CT findings in young PA patients who had unilateral adrenal disease on CT with hypokalaemia and elevation of aldosterone. DESIGN AND PATIENTS: We retrospectively studied 358 PA patients (n = 30, aged <35 years; n = 39, aged 35-40 years; n = 289, aged ≥40 years) with hypokalaemia and elevation of aldosterone and unilateral disease on CT who had successful AVS. MAIN OUTCOME MEASURE: Accuracy of CT findings is determined by AVS findings and/or surgical outcomes in patients aged <35 years. RESULTS: Concordance of the diagnosis between CT and AVS was 90% (27/30) in patients aged <35 years, 79% (31/39) in patients aged 35-40 years and 69% (198/289) in those aged ≥40 years (trend for P < .01). Surgical benefit was confirmed in three patients aged <35 years and in three patients aged 35-40 years with the available surgical data who had discordance between CT and AVS findings. Collectively, the diagnostic accuracy of CT findings was 100% (30/30) if aged <35 years and 87% (34/39) if aged 35-40 years. CONCLUSION: Primary aldosteronism patients aged <35 years with hypokalaemia and elevation of aldosterone and unilateral disease on adrenal CT could be spared AVS.

Association between severity of obstructive sleep apnea and glycated hemoglobin level in Japanese individuals with and without diabetes.

Aim of this study was to examine the association between the severity of obstructive sleep apnea (OSA) and dysglycemia in Japanese individuals with and without type 2 diabetes (T2DM). We enrolled 115 individuals diagnosed with OSA with an apnea hypopnea-index (AHI) ≥ 20 in whom continuous positive airway pressure (CPAP) therapy was introduced (N = 115, 44 with T2DM, age 62 ± 11 years, BMI 27.0 ± 4.4 kg/m2 and AHI median 36.1; interquartile range 27.2-48.1). During admission, the severity of OSA was evaluated by polysomnography, and its association with glycated hemoglobin (HbA1c) level was examined. Continuous glucose monitoring (CGM) was also conducted during the admission in 94 individuals. Apnea-hypopnea index (AHI), non-rapid eye movement (REM) AHI, minimum peripheral capillary oxygen saturation (SpO2) and percentage of sleep time (%TST) with SpO2 < 90% were significantly associated with HbA1c level in total and non-diabetic individuals (all p < 0.05) but not in those with T2DM, the majority of whom were treated with anti-diabetic medications. The associations of the non-REM AHI and %TST with SpO2 < 90% with HbA1c level remained significant after adjustment for age, sex and BMI in non-diabetic and T2DM subjects treated with dietary therapy only. Mean glucose level, but not SD or coefficient of variation of glucose, assessed by CGM was significantly associated with AHI and non-REM AHI in non-diabetic subjects after adjustment for age, sex and BMI. In conclusion, the severity of OSA was associated with increased HbA1c level independently of BMI in Japanese individuals, especially in those without diabetes.

Pulmonary nocardiosis mimicking small cell lung cancer in ectopic ACTH syndrome associated with transformation of olfactory neuroblastoma: a case report.

BACKGROUND: Pulmonary nocardiosis frequently develops as an opportunistic infection in cell-mediated immunosuppressive patients, and sometimes requires differentiation from pulmonary malignancy. Ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS) is a neoplastic disorder which leads to impaired cell-mediated immunity, and is commonly associated with small cell lung cancer (SCLC). Because pulmonary infection and causative malignancy can appear as pulmonary lesions with EAS, differentiation of these diseases remains a critical issue for physicians. CASE PRESENTATION: A 52-year-old woman with progressive lower limb paralysis and general fatigue was referred to us. She had been diagnosed with olfactory neuroblastoma (ONB) and treated with surgery and radiation therapy 10 years before the referral and had required stereotactic radiosurgery and chemotherapy 4 years later for a relapse of the ONB. On referral, she presented with Cushing's syndrome with elevated cortisol and ACTH levels. Potassium supplement improved her symptoms; however, a month later, she was urgently hospitalized due to acute pleuritic chest pain on inspiration. Chest computed tomography revealed left lower lobular consolidations and a contralateral nodule in the right middle lobe. The clinical history and laboratory work-up suggested that her Cushing's syndrome had most likely arisen from EAS. Additionally, the lungs were suspected as the ACTH source due to high levels of progastrin-releasing peptide and progressive pulmonary consolidation with a contralateral nodule, suggesting SCLC. However, histological examination from bronchoscopy revealed no evidence of malignancy, and Nocardia cyriacigeorgica was isolated from bronchoalveolar lavage fluid. Sulfamethoxazole/trimethoprim improved her pulmonary lesions. Somatostatin receptor scintigraphy revealed strong tracer uptake in the ONB lesions, indicating that the origin of the EAS was the olfactory tumor. However, histological examination of ONB specimens resected 10 years earlier showed no intracytoplasmic immunopositivity for ACTH. CONCLUSIONS: We highlight a rare case of pulmonary nocardiosis, which was associated with EAS mimicking SCLC, and was related to ONB transformation. Nocardiosis has to be considered even though anamnestic, clinical, and radiological aspects suggest the presence of metastasis. Additionally, physicians should carefully monitor patients with ONB for the development of Cushing's symptoms because the tumor can transform into an ACTH-producing form, even after long-term follow-up.

The learning curve of laparoendoscopic single-site adrenalectomy: an analysis of over 100 cases.

BACKGROUND: Recently, laparoendoscopic single-site adrenalectomy (LESS-A) has been developed as an alternative treatment for adrenal tumors. Although LESS-A is more technically complex than conventional laparoscopic adrenalectomy, its learning curve and the factors associated with poor surgical outcomes are poorly understood. We analyzed the learning curve of LESS-A and attempted to identify risk factors associated with worse surgical outcomes. METHODS: We identified 103 patients who underwent LESS-A [performed by the same surgeon (A.M.)] from 2009 to 2015. The learning curve was analyzed using the moving average method (the 10-case moving average), and we assessed potential risk factors for a prolonged pneumoperitoneum time. RESULTS: The learning curve stabilized at 30 cases. The cases were divided into two groups, the learning stage (LS) (cases 1-29) and master stage (MS) (cases 30-103) groups. The percentage of females and the frequency of previous abdominal surgery were higher in the LS group (p = 0.022 and 0.001, respectively). In the LS group, the mean pneumoperitoneum time was 92 ± 35 min, which was significantly longer than the equivalent value for the MS group (55 ± 18 min, p < 0.001). In the LS group, univariate analysis revealed that tumor size (≥50 mm) and the visceral fat area (VFA)/total fat area (TFA) ratio (≥0.49) were significantly associated with a prolonged pneumoperitoneum time (p = 0.046 and 0.046, respectively). In the multivariate analysis, tumor size and the VFA/TFA ratio were confirmed to be associated with a prolonged pneumoperitoneum time (p = 0.029 and 0.029, odds ratio 20.83 and 20.83, respectively). On the other hand, none of the examined factors were found to be associated with a prolonged pneumoperitoneum time in the MS group. CONCLUSIONS: LESS-A was performed safely in most cases. However, surgeons who are learning the LESS-A procedure need to pay attention to tumor size and visceral obesity.

A case of familial dysalbuminemic hyperthyroxinemia (FDH) in Japan: FDH as a possible differential diagnosis of syndrome of inappropriate secretion of thyroid-stimulating hormone (SITSH).

Familial dysalbuminemic hyperthyroxinemia (FDH) is an autosomal dominant condition and is the most commonly inherited euthyroid hyperthyroxinemia in Caucasians. However, it is extremely rare in Asian populations. A 30-year-old Japanese woman, who was incidentally found to have apparent thyroid dysfunction, was admitted to our hospital in 2004. She had extremely elevated serum free thyroxine (FT4), moderately elevated free triiodothyronine (FT3), and normal thyroid-stimulating hormone (TSH). Clinical thyroid examination revealed no abnormalities other than small goiter. Anti-thyroglobulin antibody titer was positive, but titers of other anti-thyroid antibodies, including antithyroid peroxidase antibody, TSH receptor antibodies, and thyroid-stimulating antibody, were negative. Levels of FT3, FT4, and TSH were similar when measured by three different laboratory kits, and FT4 was still high when measured by equilibrium dialysis. By affinity chromatography, FT4, TT4, and albumin were extracted to the same fraction, and the levels of FT4 and TT4 were extremely high. By combination of reversed phase liquid chromatography and mass spectrometry techniques, the amino acid sequence of human serum albumin was determined. The patient was found to be a heterozygote for p.R218P mutation in the gene for human serum albumin and was diagnosed as FDH. This patient, who harbored the p.R218P mutation in the albumin gene, is the fifth case report of FDH in Japan. This condition is characterized by extremely high serum FT4 and moderately high serum FT3 levels. Although rare, FDH should be considered in the differential diagnosis for syndrome of inappropriate secretion of TSH (SITSH) in Japan.

High Glucose Stimulates Mineralocorticoid Receptor Transcriptional Activity Through the Protein Kinase C ß Signaling.

Activation of mineralocorticoid receptor (MR) is shown in resistant hypertension including diabetes mellitus. Although protein kinase C (PKC) signaling is involved in the pathogenesis of diabetic complications, an association between PKC and MR is not known. Activation of PKCα and PKCß by TPA (12-O-Tetradecanoylphorbol 13-acetate) increased MR proteins and its transcriptional activities in HEK293-MR cells. In contrast, a high glucose condition resulted in PKCß but not PKCα activation, which is associated with elevation of MR protein levels and MR transcriptional activities. Reduction of endogenous PKCß by siRNA decreased those levels. Interestingly, high glucose did not affect MR mRNA levels, but rather decreased ubiquitination of MR proteins. In db/db mice kidneys, levels of phosphorylated PKCß2, MR and Sgk-1 proteins were elevated, and the administration of PKC inhibitor reversed these changes compared to db/+ mice. These data suggest that high glucose stimulates PKCß signaling, which leads to MR stabilization and its transcriptional activities.

Calibration and evaluation of routine methods by serum certified reference material for aldosterone measurement in blood.

We attempted to study the standardization of aldosterone measurement in blood. The serum certified reference material (serum CRM) was established by spiking healthy human serum with pure aldosterone. ID-LC/MS/MS as a reference measurement procedure was performed by using the serum CRM. LC-MS/MS as a comparison method (CM) was routinely used for clinical samples, and the values with and without calibration by the serum CRM were compared. The serum CRM demonstrated similar reactivity with peripheral blood plasma as clinical samples in routine methods (RM) of RIA, ELISA, and CLEIA. In comparison between RM and CM, the results in regression analysis indicated that the range of the correlation coefficient (r) was 0.913 - 0.991, the range of y intercept was 0.9 - 67.3 pg/mL and the range of slope was 0.869 - 1.174. The values by RM in 100 - 150 pg/mL for the diagnostic level, had a significant calibration effect, and the relative difference between calibrated value in RM and result by CM was within ±20%. Furthermore, the calibrated value using the serum CRM was 10,187 pg/mL, which corresponds to measured value of 14,000 pg/mL using RIA for the adrenal venous sampling. Measured values between plasma and serum as a sample for the aldosterone measurement from clinical samples showed no significant differences. In conclusion, we succeeded to prepare the certified reference material of aldosterone for RM. Then, we can accurately calculate corrected values by using our equation for four RMs of determination of aldosterone.

CT during Arteriography to Visualize the Right Adrenal Vein for Adrenal Venous Sampling.

The present report describes 6 cases of adrenal venous sampling (AVS) in patients who underwent computed tomography (CT) during arteriography because cannulation of right adrenal veins was otherwise difficult. CT was performed during arteriography to obtain information on the location and direction of the right adrenal vein. Two right adrenal veins were visualized in 1 case. The right central adrenal vein was not visualized in 1 case owing to an injury from a previous unsuccessful AVS procedure, but the right renal capsular vein was well visualized. CT during arteriography could contribute to a high AVS success rate.