Identifying primary aldosteronism patients who require adrenal venous sampling: a multi-center study.

Adrenal venous sampling (AVS) is crucial for subtyping primary aldosteronism (PA) to explore the possibility of curing hypertension. Because AVS availability is limited, efforts have been made to develop strategies to bypass it. However, it has so far proven unsuccessful in applying clinical practice, partly due to heterogeneity and missing values of the cohorts. For this purpose, we retrospectively assessed 210 PA cases from three institutions where segment-selective AVS, which is more accurate and sensitive for detecting PA cases with surgical indications, was available. A machine learning-based classification model featuring a new cross-center domain adaptation capability was developed. The model identified 102 patients with PA who benefited from surgery in the present cohort. A new data imputation technique was used to address cross-center heterogeneity, making a common prediction model applicable across multiple cohorts. Logistic regression demonstrated higher accuracy than Random Forest and Deep Learning [(0.89, 0.86) vs. (0.84, 0.84), (0.82, 0.84) for surgical or medical indications in terms of f-score]. A derived integrated flowchart revealed that 35.2% of PA cases required AVS with 94.1% accuracy. The present model enabled us to reduce the burden of AVS on patients who would benefit the most.

Impact of primary aldosteronism on renal function in patients with type 2 diabetes.

AIMS/INTRODUCTION: Renal dysfunction might quickly progress in patients with type 2 diabetes mellitus, when accompanied by hypertension. However, whether primary aldosteronism (PA), which autonomously over-secretes aldosterone, causes additional renal damage in patients with type 2 diabetes mellitus is unclear. We evaluated the impact of PA on renal function in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: A retrospective review of all patients with type 2 diabetes mellitus who visited Yokohama Rosai Hospital's (Yokohama Japan) outpatient department between April 2017 and March 2018 was carried out. Records of patients with PA who underwent PA treatment by adrenalectomy or mineralocorticoid receptor antagonists (PA group) and those without PA (non-PA group) were extracted, and renal function was compared between the two groups. Untreated PA patients were excluded, as their renal function might be overestimated as a result of glomerular hyperfiltration. RESULTS: There were 83 patients in the PA group and 1,580 patients in the non-PA group. The PA group had significantly lower estimated glomerular filtration rates than the non-PA group (66.3 [52.4-78.2] vs 70.5 [56.0-85.6] mL/min/1.73 m2 , P = 0.047). Multiple regression analysis showed that PA was a factor for decreased estimated glomerular filtration rate, independent of age, sex, glycated hemoglobin, diuretic use and hypertension (P = 0.025). PA induced a 3.7-mL/min/1.73 m2 (95% confidence interval 0.47-6.9) decrease in estimated glomerular filtration rate, equivalent to that induced by 4.4 years of aging. CONCLUSIONS: Our results show that in patients with type 2 diabetes mellitus, PA is an independent risk factor for renal dysfunction. To prevent the progression of renal failure, PA should not be overlooked.

Precise Mapping of Intra-Adrenal Aldosterone Activities Provides a Novel Surgical Strategy for Primary Aldosteronism.

Segmental selective adrenal venous sampling (sAVS) elucidates an intraadrenal aldosterone activity map (IAMap), which allows us to design a novel surgical treatment strategy for patients with primary aldosteronism. We evaluated the usefulness of sAVS by analyzing 278 patients with whom we had prospectively used IAMap using the criteria of sAVS for surgical indication between 2009 and 2015. We evaluated its diagnostic accuracy using pathological and postsurgical biochemical and clinical outcomes. One hundred twenty and 158 patients were diagnosed with unilateral and bilateral disease, respectively, through sAVS. The concordance of lateralization diagnosis with computed tomography imaging was 66.6%. Among the unilateral patients, we performed partial adrenalectomy in 68 patients whose IAMap showed focal aldosterone hypersecretion from computed tomography-detectable tumor in the affected adrenal gland. All of them achieved complete biochemical success 1 year after surgery. Furthermore, 25 of 158 bilateral disease patients underwent surgical resection because they were preoperatively diagnosed as bilateral aldosterone-producing adenomas by IAMap. These cases showed complete or partial biochemical success (28.0% and 72.0%, respectively); 36.0% showed complete clinical success. Pathological studies demonstrated that all 145 resected specimens possessed aldosterone-producing adenoma or multiple nodules (132 and 13 cases, respectively), and none showed diffuse hyperplasia. IAMap accurately diagnosed both bilateral and unilateral aldosterone-producing adenomas and diffuse hyperplasia before surgery. sAVS allows a novel surgical strategy for selected PA patients with favorable outcomes.

A Patient with Nivolumab-related Fulminant Type 1 Diabetes Mellitus whose Serum C-peptide Level Was Preserved at the Initial Detection of Hyperglycemia.

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.

Changes in glucose metabolism based on 75-g oral glucose tolerance tests before and after surgery for adrenal Cushing's syndrome.

Adrenal Cushing's syndrome (CS) is caused by cortisol-producing adrenal adenoma and is frequently accompanied by glucose metabolism disorders, which are characterized by increased insulin resistance and insufficient ß-cell compensation. However, considering the rarity of CS, few studies have assessed whether the glucose metabolism disorders could be ameliorated by surgical treatment. In this case series, we evaluated glucose metabolism before and after surgery in 11 patients (10 women and 1 man) who underwent unilateral adrenalectomy for overt adrenal CS between 2005 and 2016. Patients with pre-diagnosed diabetes mellitus (DM) were excluded. Pre- and post-operative 75-g oral glucose tolerance tests were performed. Cortisol secretion decreased significantly after surgery (median 24-h urinary free cortisol: 582.0 µg/day [interquartile range: 321.0-743.0 µg/day] to 31.3 µg/day [23.6-40.6 µg/day], p = 0.001). The results of the OGTT generally improved after surgery (normal glucose tolerance/impaired glucose tolerance/DM: 2/8/1 to 8/3/0), with significant decreases in the immunoreactive insulin and glucose levels. We also found a decrease in the median homeostatic model assessment of insulin resistance (2.4 [1.4-2.8] to 1.0 [0.6-1.1], p = 0.002), and increases in the median Matsuda index (3.0 [2.3-4.5] to 8.2 [6.3-11.4], p < 0.001), median insulinogenic index (0.70 [0.22-1.51] to 1.22 [0.78-1.64], p = 0.08), and median disposition index (609.1 [237.8-1,095.2] to 1,286.0 [1,034.6-1,857.6], p = 0.002). These findings indicate that adrenalectomy for adrenal CS without overt DM may help ameliorate glucose metabolism disorders, and improve both insulin resistance and insulin secretion.

Prednisolone-responsive Postpartum IgG4-related Hypophysitis.

We herein report the case of a 25-year-old woman who presented with severe headache and visual field defects after childbirth. Magnetic resonance imaging revealed marked swelling of the pituitary gland, and an endocrinological examination revealed panhypopituitarism and diabetes insipidus. An immunohistological analysis of a transsphenoidal biopsy sample of the pituitary gland showed the significant accumulation of an immunogloblin G4 (IgG4)-positive population, leading to the diagnosis of IgG4-related hypophysitis. The patient was treated with prednisolone, which markedly reduced the swelling of the pituitary gland, in association with recovery of the pituitary function. This is a rare case of biopsy-proven IgG4-related hypophysitis with a postpartum onset.

Multihormonal pituitary adenoma concomitant with Pit-1 and Tpit lineage cells causing acromegaly associated with subclinical Cushing's disease: a case report.

BACKGROUND: A functional pituitary adenoma can produce multiple anterior-pituitary hormones, such as growth hormone (GH) -producing adenomas (GHoma) with prolactin or thyrotropin stimulating hormone production in the same lineage. However, it is very rare that acromegaly shows subclinical Cushing's disease (SCD) beyond the lineage. Here we describe the involvement of intratumoral coexistence with 2 types of hormone-producing cells associated with different lineage in acromegaly concomitant with SCD. CASE PRESENTATION: In our study, we performed clinical evaluation of the patient showing acromegaly with SCD. To elucidate the mechanisms of this pathology, we analyzed immunohistochemistry and gene expression of anterior-pituitary hormones and transcriptional factors in the resected pituitary tumor. On immunohistochemical staining, most of the tumor cells were strongly stained for GH antibody, while some cells were strongly positive for adrenocorticotropic hormone (ACTH). Gene expression analysis of a transsphenoidal surgery sample of the pituitary gland revealed that ACTH-related genes, such as POMC, Tpit, and NeuroD1 mRNA, had higher expression in the tumor tissue than the nonfunctional adenoma but lower expression compared to an adenoma of typical Cushing's disease. Further, double-labeling detection methods with a fluorescent stain for ACTH and GH demonstrated the coexistence of ACTH-positive cells (GH-negative) among the GH-positive cells in the tumor. Additionally, Pit-1 expression was reduced in the ACTH-positive cells from tumor tissue primary culture. CONCLUSION: Here we described a case of a pituitary tumor diagnosed with acromegaly associated with SCD. We performed quantitative-expression analyses of transcriptional factors of the tumor tissue and immunohistochemistry analysis of tumor-derived primary culture cells, which suggested that the multihormonal pituitary adenoma concomitant with Pit-1 and Tpit lineage cells caused acromegaly associated with SCD.

SEVEN FAMILIAL DYSALBUMINEMIC HYPERTHYROXINEMIA CASES IN THREE UNRELATED JAPANESE FAMILIES AND HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY ANALYSIS OF THE THYROXINE BINDING PROFILE.

OBJECTIVE: Familial dysalbuminemic hyperthyroxinemia (FDH) is caused by abnormal human serum albumin (HSA) with an increased thyroxine (T4) affinity leading to euthyroid hyperthyroxinemia. One- and 2-step immunoassays of serum samples from FDH patients (e.g., Japanese patients) with the HSA R218P mutation can yield false-positive free thyroxine (FT4) results. Therefore, it is difficult to distinguish FDH from syndrome of inappropriate secretion of thyroid-stimulating hormone (TSH) (e.g., syndrome of resistance to thyroid hormone, TSH-producing pituitary adenoma), even when multiple assays are used. To investigate T4 to HSA binding, we examined serum samples from 7 patients from 3 Japanese families with FDH. Clinically, abnormal thyroid function tests were noted in pregnant Patient 1. Patients 2 and 3 had histories of inappropriate treatment with antithyroid drugs and surgery. METHODS: All patients and affected family members were diagnosed with FDH using direct sequencing analysis. Gel filtration high-performance liquid chromatography was used for the biochemical analyses. RESULTS: The genomic analysis revealed a heterozygous missense mutation in HSA (R218P). In FDH patient sera, the albumin effluent corresponded to the peaks for total T4 (TT4); approximately 60% of the T4 in the effluent was detected as FT4. The results for the albumin effluent from healthy volunteer and TSHoma patient sera showed no corresponding TT4 peak. CONCLUSION: In the FDH patients, a relatively larger quantity of T4 was bound to abnormal HSA. This bound T4 was measured as FT4 during the analysis. ABBREVIATIONS: F = free; FDH = familial dysalbuminemic hyperthyroxinemia; HPLC = high-performance liquid chromatography; HSA = human serum albumin; PCR = polymerase chain reaction; SITSH = syndrome of inappropriate secretion of TSH; T = total; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WT = wild-type.

Cushing Syndrome Due to ACTH-Secreting Pheochromocytoma, Aggravated by Glucocorticoid-Driven Positive-Feedback Loop.

CONTEXT: Pheochromocytoma is a catecholamine-producing tumor that originates from adrenal chromaffin cells and is capable of secreting various hormones, including ACTH. CASE DESCRIPTION: A 56-year-old female presented with Cushingoid appearance and diabetic ketoacidosis. Endocrinological examinations demonstrated ectopic ACTH production with hypercortisolemia and excess urinary cortisol accompanied by elevated plasma and urine catecholamines. Computed tomography revealed a large left adrenal tumor with bilateral adrenal enlargement. Metaiodobenzylguanidine scintigraphy revealed abnormal accumulation in the tumor, which was eventually diagnosed as pheochromocytoma with ectopic ACTH secretion with subsequent manifestation of Cushing's syndrome. Ectopic ACTH secretion and catecholamine production were blocked by metyrapone treatment, whereas dexamethasone paradoxically increased ACTH secretion. Left adrenalectomy resulted in complete remission of Cushing's syndrome and pheochromocytoma. IN VITRO STUDIES: Immunohistological analysis revealed that the tumor contained two functionally distinct chromaffin-like cell types. The majority of tumor cells stained positive for tyrosine hydroxylase (TH), whereas a minor population of ACTH-positive tumor cells was negative for TH. Furthermore, gene expression and in vitro functional analyses using primary tumor tissue cultures demonstrated that dexamethasone facilitated ACTH as well as catecholamine secretion with parallel induction of proopiomelanocortin (POMC), TH, and phenylethanolamine N-methyltransferase mRNA, supporting a glucocorticoid-dependent positive-feedback loop of ACTH secretion in vivo. DNA methylation analysis revealed that the POMC promoter of this tumor, particularly the E2F binding site, was hypomethylated. CONCLUSION: We present a case of ectopic ACTH syndrome associated with pheochromocytoma. ACTH up-regulation with paradoxical response to glucocorticoid, possibly through the hypomethylation of the POMC promoter, exacerbated the patient's condition.

Clinical predictors of prolonged postresection hypotension after laparoscopic adrenalectomy for pheochromocytoma.

BACKGROUND: Although the perioperative management of patients with pheochromocytoma has been improving recently, severe hypotensive episodes can occur that require postoperative catecholamine support and are challenging to manage. Our aim was to identify the clinical factors that predict prolonged postresection hypotension in patients after laparoscopic adrenalectomy for pheochromocytoma. METHODS: The records of 73 Japanese patients who underwent unilateral laparoscopic adrenalectomy for pheochromocytoma were surveyed retrospectively. Patients were divided into 2 groups according to whether catecholamine support was needed after postoperatively. Clinical and biochemical data were evaluated at baseline and after operation. RESULTS: Thirty-four of 73 patients (47%) required continuous infusion of catecholamine to maintain systolic blood pressure >90 mm Hg at the end of the operation. The median duration of postoperative catecholamine support was 17 hours (range, 3-130) in these 34 patients. On multivariate analysis, tumor size >60 mm, urinary epinephrine levels >200 µg/day, and urinary norepinephrine levels >600 µg/day were independent predictors of prolonged hypotension requiring postoperative catecholamine support. Tumor size and urinary norepinephrine levels were significantly correlated with the duration of postoperative catecholamine support. CONCLUSION: Larger tumor size and greater values of urinary epinephrine and norepinephrine levels were significant predictors of prolonged hypotension requiring postoperative catecholamine support. Moreover, tumor size and urinary norepinephrine levels were positively correlated with the duration of postoperative catecholamine support. Clinicians can identify and manage patients more effectively with a greater risk of prolonged hypotension after tumor resection using these preoperative clinical variables.

GERMLINE DELETION OF ARMC5 IN FAMILIAL PRIMARY MACRONODULAR ADRENAL HYPERPLASIA.

OBJECTIVE: Primary macronodular adrenal hyperplasia (PMAH) is considered a predominantly sporadic disease, but familial forms are well recognized. Genetic studies revealed germline mutations in the armadillo repeat containing 5 gene (ARMC5) in the majority of PMAH cases. Furthermore, somatic ARMC5 mutations, as different types of second-hit mutations and loss of heterozygosity have been reported in each adrenal nodule in PMAH. Here, we describe the involvement of ARMC5 alteration in a familial case of PMAH. METHODS: In our study, we performed clinical and genetic evaluations in a mother and her son with familial PMAH. To search for mutations and deletion of ARMC5, we used Sanger sequencing and droplet digital polymerase chain reaction (ddPCR), respectively. RESULTS: Both patients showed the same phenotype of subclinical Cushing syndrome, with mild excess of mineralocorticoids and vasopressin-responsive cortisol secretion. The ddPCR analysis demonstrated that both mother and son had germline deletions in exons 1 to 5 of the ARMC5 gene locus. Furthermore, Sanger sequencing of DNA from the right and left adrenal nodules as well as peripheral blood of the son revealed the presence of another germline, missense mutation in ARMC5 exon 3 (p.P347S). CONCLUSION: This is the first report demonstrating germline deletion of ARMC5 in familial PMAH. In addition to investigating mutations, germline and somatic deletions of ARMC5 could be examined by ddPCR, which permits rapid and accurate evaluation of the ARMC5 allelic status.

Increased level of polyploidy1, a conserved repressor of CYCLINA2 transcription, controls endoreduplication in Arabidopsis.

Endoreduplication is a type of cell cycle in which DNA replication continues without cell division. We have isolated several dominant mutants from Arabidopsis thaliana activation tagging lines by flow cytometry. One of the mutants, increased level of polyploidy1-1D (ilp1-1D), showed increased polyploidy in both light- and dark-grown hypocotyls. The corresponding gene of ilp1-1D encodes a protein homologous to the C-terminal region of mammalian GC binding factor. We demonstrate that this protein functions as a transcriptional repressor in vivo. The expression of all members of the CYCLINA2 (CYCA2) family was reduced in an ILP1 overexpressing line, and the mouse (Mus musculus) homolog of ILP1 repressed cyclin A2 expression in mouse NIH3T3 cells. T-DNA insertion mutants of ILP1 showed reduced polyploidy and upregulated all CYCA2 expression. Furthermore, loss of CYCA2;1 expression induces an increase in polyploidy in Arabidopsis. We demonstrate that this protein regulates endoreduplication through control of CYCA2 expression in Arabidopsis.