Adrenal insufficiency (AI) can be classified into three distinct categories based on its underlying causes: primary adrenal disorders, secondary deficiencies in adrenocorticotropin, or hypothalamic suppression from external factors, most commonly glucocorticoid medications used for anti-inflammatory therapy. The hallmark clinical features of AI include fatigue, appetite loss, unintentional weight loss, low blood pressure, and hyponatremia. Individuals with primary AI additionally manifest skin hyperpigmentation, hyperkalemia, and salt craving. The diagnosis of AI is frequently delayed due to the non-specific symptoms and signs early in the disease course, which poses a significant challenge to its early detection prior to an adrenal crisis. Despite the widespread availability of lifesaving glucocorticoid medications for decades, notable challenges persist, particularly in the domains of timely diagnosis while simultaneously avoiding misdiagnosis, patient education for averting adrenal crises, and the determination of optimal replacement therapies. This article reviews recent advancements in the contemporary diagnostic strategy and approaches to optimal treatment for AI.
Background This study investigated the incidence of endocrine immune-related adverse events (irAEs) for recently developed immune checkpoint inhibitor (ICI) drugs.
Methods We collected studies on newly developed ICI drugs using PubMed/Medline, Embase, and Cochrane Library from inception through January 31, 2023. Among ICI drugs, nivolumab, pembrolizumab, and ipilimumab were excluded from the new ICI drugs because many papers on endocrine-related side effects have already been published.
Results A total of 44,595 patients from 177 studies were included in this analysis. The incidence of hypothyroidism was 10.1% (95% confidence interval [CI], 8.9% to 11.4%), thyrotoxicosis was 4.6% (95% CI, 3.8% to 5.7%), hypophysitis was 0.8% (95% CI, 0.5% to 1.1%), adrenal insufficiency was 0.9% (95% CI, 0.7% to 1.1%), and hyperglycemia was 2.3% (95% CI, 1.6% to 3.4%). Hypothyroidism and thyrotoxicosis occurred most frequently with programmed cell death protein-1 (PD-1) inhibitors (13.7% and 7.5%, respectively). The rate of endocrine side effects for the combination of a programmed death-ligand 1 inhibitor (durvalumab) and cytotoxic T lymphocyte-associated antigen 4 inhibitor (tremelimumab) was higher than that of monotherapy. In a meta-analysis, the combination of tremelimumab and durvalumab had a 9- to 10-fold higher risk of pituitary and adrenal-related side effects than durvalumab alone.
Conclusion Newly developed PD-1 inhibitors had a high incidence of thyroid-related irAEs, and combined treatment with durvalumab and tremelimumab increased the risk of pituitary- and adrenal-related irAEs. Based on these facts, it is necessary to predict the endocrine side effects corresponding to each ICI drug, diagnose and treat them appropriately, and try to reduce the morbidity and mortality of patients.
Adrenal incidentalomas represent an increasingly common clinical conundrum with significant implications for patients. The revised 2023 European Society of Endocrinology (ESE) guideline incorporates cutting-edge evidence for managing adrenal incidentalomas. This paper provides a concise review of the updated contents of the revised guideline. In the 2023 guideline, in patients without signs and symptoms of overt Cushing’s syndrome, a post-dexamethasone cortisol level above 50 nmol/L (>1.8 μg/dL) should be considered as mild autonomous cortisol secretion. Regarding the criteria of benign adrenal adenomas, a homogeneous adrenal mass with ≤10 Hounsfield units on non-contrast computed tomography requires no further follow-up, irrespective of its size. The updated guideline also discusses steroid metabolomics using tandem mass spectrometry to discriminate malignancy. It underscores the importance of high-volume surgeons performing adrenalectomy and emphasizes the pivotal role of a multidisciplinary team approach in deciding the treatment plan for indeterminate adrenal masses. The guideline advocates for more proactive surgical treatment for indeterminate adrenal masses in young patients (<40 years) and pregnant women. This review of the 2023 ESE guideline underscores the ongoing evolution of the adrenal incidentaloma management landscape, emphasizing the need for further research and adaptation of diagnostic and therapeutic strategies.
Hyemi Kwon, Eun Roh, Chang Ho Ahn, Hee Kyung Kim, Cheol Ryong Ku, Kyong Yeun Jung, Ju Hee Lee, Eun Heui Kim, Sunghwan Suh, Sangmo Hong, Jeonghoon Ha, Jun Sung Moon, Jin Hwa Kim, Mi-kyung Kim, The Committee of Clinical Practice Guideline of the Korean Endocrine Society
Endocrinol Metab. 2022;37(6):839-850. Published online December 26, 2022
Immune checkpoint inhibitors (ICIs) including an anti-cytotoxic T-lymphocyte-associated antigen 4 inhibitor, anti-programmed cell death protein 1 (PD-1) inhibitors, and anti-PD-ligand 1 inhibitors are representative therapeutics for various malignancies. In oncology, the application of ICIs is currently expanding to a wider range of malignancies due to their remarkable clinical outcomes. ICIs target immune checkpoints which suppress the activity of T-cells that are specific for tumor antigens, thereby allowing tumor cells to escape the immune response. However, immune checkpoints also play a crucial role in preventing autoimmune reactions. Therefore, ICIs targeting immune checkpoints can trigger various immune-related adverse events (irAEs), especially in endocrine organs. Considering the endocrine organs that are frequently involved, irAEs associated endocrinopathies are frequently life-threatening and have unfavorable clinical implications for patients. However, there are very limited data from large clinical trials that would inform the development of clinical guidelines for patients with irAEs associated endocrinopathies. Considering the current clinical situation, in which the scope and scale of the application of ICIs are increasing, position statements from clinical specialists play an essential role in providing the appropriate recommendations based on both medical evidence and clinical experience. As endocrinologists, we would like to present precautions and recommendations for the management of immune-related endocrine disorders, especially those involving the adrenal, thyroid, and pituitary glands caused by ICIs.
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Pembrolizumab plus lenvatinib for radically unresectable or metastatic renal cell carcinoma in the Japanese population Ryo Fujiwara, Takeshi yuasa, kenichi kobayashi, tetsuya yoshida, susumu kageyama Expert Review of Anticancer Therapy.2023; 23(5): 461. CrossRef
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Accurate measurement of cortisol is critical in adrenal insufficiency as it reduces the risk associated with misdiagnosis and supports the optimization of stress dose. Comprehensive assays have been developed to determine the levels of bioactive free cortisol and their clinical and analytical efficacies have been extensively discussed because the level of total cortisol is affected by changes in the structure or circulating levels of corticoid-binding globulin and albumin, which are the main reservoirs of cortisol in the human body. Antibody-based immunoassays are routinely used in clinical laboratories; however, the lack of molecular specificity in cortisol assessment limits their applicability to characterize adrenocortical function. Improved specificity and sensitivity can be achieved by mass spectrometry coupled with chromatographic separation methods, which is a cutting-edge technology to measure individual as well as a panel of steroids in a single analytical run. The purpose of this review is to introduce recent advances in free cortisol measurement from the perspectives of clinical specimens and issues associated with prospective analytical technologies.
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Determination of cortisol cut-off limits and steroid dynamics in the ACTH stimulation test: a comparative analysis using Roche Elecsys Cortisol II immunoassay and LC-MS/MS Sema Okutan, Nanna Thurmann Jørgensen, Lars Engers Pedersen, Stina Willemoes Borresen, Linda Hilsted, Lennart Friis Hansen, Ulla Feldt-Rasmussen, Marianne Klose Endocrine.2024;[Epub] CrossRef
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Electrochemical sensors for cortisol detection: Principles, designs, fabrication, and characterisation Gopi Karuppaiah, Min-Ho Lee, Shekhar Bhansali, Pandiaraj Manickam Biosensors and Bioelectronics.2023; 239: 115600. CrossRef
The role of the hypothalamic-pituitary-adrenal axis in depression across the female reproductive lifecycle: current knowledge and future directions Liisa Hantsoo, Kathleen M. Jagodnik, Andrew M. Novick, Ritika Baweja, Teresa Lanza di Scalea, Aysegul Ozerdem, Erin C. McGlade, Diana I. Simeonova, Sharon Dekel, Sara L. Kornfield, Michelle Nazareth, Sandra J. Weiss Frontiers in Endocrinology.2023;[Epub] CrossRef
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Corticotropin-stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study Josef Briegel, Patrick Möhnle, Didier Keh, Johanna M. Lindner, Anna C. Vetter, Holger Bogatsch, Dorothea Lange, Sandra Frank, Ludwig C. Hinske, Djillali Annane, Michael Vogeser, Michael Bauer, Thorsten Brenner, Patrick Meybohm, Markus Weigand, Matthias Gr Critical Care.2022;[Epub] CrossRef
Jung Hee Kim, Chang Ho Ahn, Su Jin Kim, Kyu Eun Lee, Jong Woo Kim, Hyun-Ki Yoon, Yu-Mi Lee, Tae-Yon Sung, Sang Wan Kim, Chan Soo Shin, Jung-Min Koh, Seung Hun Lee
Endocrinol Metab. 2022;37(2):369-382. Published online April 14, 2022
Background Optimal management of primary aldosteronism (PA) is crucial due to the increased risk of cardiovascular and cerebrovascular diseases. Adrenal venous sampling (AVS) is the gold standard method for determining subtype but is technically challenging and invasive. Some PA patients do not benefit clinically from surgery. We sought to develop an algorithm to improve decision- making before engaging in AVS and surgery in clinical practice.
Methods We conducted the ongoing Korean Primary Aldosteronism Study at two tertiary centers. Study A involved PA patients with successful catheterization and a unilateral nodule on computed tomography and aimed to predict unilateral aldosterone-producing adenoma (n=367). Study B involved similar patients who underwent adrenalectomy and aimed to predict postoperative outcome (n=330). In study A, we implemented important feature selection using the least absolute shrinkage and selection operator regression.
Results We developed a unilateral PA prediction model using logistic regression analysis: lowest serum potassium level ≤3.4 mEq/L, aldosterone-to-renin ratio ≥150, plasma aldosterone concentration ≥30 ng/mL, and body mass index <25 kg/m2 (area under the curve, 0.819; 95% confidence interval, 0.774 to 0.865; sensitivity, 97.6%; specificity, 25.5%). In study B, we identified female, hypertension duration <5 years, anti-hypertension medication <2.5 daily defined dose, and the absence of coronary artery disease as predictors of clinical success, using stepwise logistic regression models (sensitivity, 94.2%; specificity, 49.3%). We validated our algorithm in the independent validation dataset (n=53).
Conclusion We propose this new outcome-driven diagnostic algorithm, simultaneously considering unilateral aldosterone excess and clinical surgical benefits in PA patients.
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Subtype-specific Body Composition and Metabolic Risk in Patients With Primary Aldosteronism Seung Shin Park, Chang Ho Ahn, Sang Wan Kim, Ji Won Yoon, Jung Hee Kim The Journal of Clinical Endocrinology & Metabolism.2024; 109(2): e788. CrossRef
Prognostic models to predict complete resolution of hypertension after adrenalectomy in primary aldosteronism: A systematic review and meta‐analysis Luigi Marzano, Amir Kazory, Faeq Husain‐Syed, Claudio Ronco Clinical Endocrinology.2023; 99(1): 17. CrossRef
2023 Korean Endocrine Society Consensus Guidelines for the Diagnosis and Management of Primary Aldosteronism Jeonghoon Ha, Jung Hwan Park, Kyoung Jin Kim, Jung Hee Kim, Kyong Yeun Jung, Jeongmin Lee, Jong Han Choi, Seung Hun Lee, Namki Hong, Jung Soo Lim, Byung Kwan Park, Jung-Han Kim, Kyeong Cheon Jung, Jooyoung Cho, Mi-kyung Kim, Choon Hee Chung Endocrinology and Metabolism.2023; 38(6): 597. CrossRef
Correlation of Histopathologic Subtypes of Primary Aldosteronism with Clinical Phenotypes and Postsurgical Outcomes Chang Ho Ahn, You-Bin Lee, Jae Hyeon Kim, Young Lyun Oh, Jung Hee Kim, Kyeong Cheon Jung The Journal of Clinical Endocrinology & Metabolism.2023;[Epub] CrossRef
Adrenal Gland Big Data Articles (National Health Insurance Service Database)
Background Previous studies on the epidemiology and complications of congenital adrenal hyperplasia (CAH) were conducted in Western countries and in children/adolescents. We aimed to explore the epidemiology of CAH, as well as the risk of comorbidities and mortality, in a Korean nationwide case-control study.
Methods CAH patients (n=2,840) were included between 2002 and 2017 from the National Health Insurance Service database and the Rare Intractable Disease program. CAH patients were compared, at a 1:10 ratio, with age-, sex-, and index year-matched controls (n=28,400).
Results The point prevalence of CAH patients in Korea was 1 in 18,745 persons in 2017. The annual incidence rate declined between 2003 and 2017 from 3.25 to 0.41 per 100,000 persons. CAH patients were at elevated risk for cardiovascular disease (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.4 to 1.9), stroke (OR, 1.7; 95% CI, 1.3 to 2.0), diabetes mellitus (OR, 2.8; 95% CI, 2.6 to 3.1), dyslipidemia (OR, 2.4; 95% CI, 2.2 to 2.6), and psychiatric disorders (OR, 1.5; 95% CI, 1.3 to 1.6). Fracture risk increased in CAH patients aged over 40 years (OR, 1.4; 95% CI, 1.1 to 1.7). CAH patients were at higher risk of mortality than controls (hazard ratio, 1.6; 95% CI, 1.3 to 2.0).
Conclusion Our nationwide study showed a recent decline in the incidence of CAH and an elevated risk for cardiovascular, metabolic, skeletal, and psychiatric disorders in CAH patients. Lifelong management for comorbidity risk is a crucial component of treating CAH patients.
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Hyperandrogenism and Cardiometabolic Risk in Pre- and Postmenopausal Women—What Is the Evidence? Angelica Lindén Hirschberg The Journal of Clinical Endocrinology & Metabolism.2024; 109(5): 1202. CrossRef
Predictors of Cardiovascular Morbidities in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia Suranut Charoensri, Richard J Auchus The Journal of Clinical Endocrinology & Metabolism.2024; 109(3): e1133. CrossRef
Case report: Development of central precocious puberty in a girl with late-diagnosed simple virilizing congenital adrenal hyperplasia complicated with Williams syndrome Eun Young Joo, Myung Ji Yoo, Su Jin Kim, Woori Jang, Ji-Eun Lee Frontiers in Endocrinology.2024;[Epub] CrossRef
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Big Data Research in the Field of Endocrine Diseases Using the Korean National Health Information Database Sun Wook Cho, Jung Hee Kim, Han Seok Choi, Hwa Young Ahn, Mee Kyoung Kim, Eun Jung Rhee Endocrinology and Metabolism.2023; 38(1): 10. CrossRef
Long-term cardiometabolic morbidity in young adults with classic 21-hydroxylase deficiency congenital adrenal hyperplasia Beatrice Righi, Salma R. Ali, Jillian Bryce, Jeremy W. Tomlinson, Walter Bonfig, Federico Baronio, Eduardo C. Costa, Guilherme Guaragna-Filho, Guy T’Sjoen, Martine Cools, Renata Markosyan, Tania A. S. S. Bachega, Mirela C. Miranda, Violeta Iotova, Henrik Endocrine.2023; 80(3): 630. CrossRef
Serum steroid profile captures metabolic phenotypes in adults with classic congenital adrenal hyperplasia Chang Ho Ahn, Jaeyoon Shim, Han Na Jang, Young Ah Lee, Sang-Won Lee, Man Ho Choi, Jung Hee Kim The Journal of Steroid Biochemistry and Molecular Biology.2023; 234: 106374. CrossRef
Long‐term health consequences of congenital adrenal hyperplasia Riccardo Pofi, Xiaochen Ji, Nils P. Krone, Jeremy W. Tomlinson Clinical Endocrinology.2023;[Epub] CrossRef
Multiplexed Serum Steroid Profiling Reveals Metabolic Signatures of Subtypes in Congenital Adrenal Hyperplasia Jaeyoon Shim, Chang Ho Ahn, Seung Shin Park, Jongsung Noh, Chaelin Lee, Sang Won Lee, Jung Hee Kim, Man Ho Choi Journal of the Endocrine Society.2023;[Epub] CrossRef
Long-Term Outcomes of Congenital Adrenal Hyperplasia Anna Nordenström, Svetlana Lajic, Henrik Falhammar Endocrinology and Metabolism.2022; 37(4): 587. CrossRef
Background Monitoring adults with classical 21-hydroxylase deficiency (21OHD) is challenging due to variation in clinical and laboratory settings. Moreover, guidelines for adrenal imaging in 21OHD are not yet available. We evaluated the relationship between adrenal morphology and disease control status in classical 21OHD.
Methods This retrospective, cross-sectional study included 90 adult 21OHD patients and 270 age- and sex-matched healthy controls. We assessed adrenal volume, width, and tumor presence using abdominal computed tomography and evaluated correlations of adrenal volume and width with hormonal status. We investigated the diagnostic performance of adrenal volume and width for identifying well-controlled status in 21OHD patients (17α-hydroxyprogesterone [17-OHP] <10 ng/mL).
Results The adrenal morphology of 21OHD patients showed hypertrophy (45.6%), normal size (42.2%), and hypotrophy (12.2%). Adrenal tumors were detected in 12 patients (13.3%). The adrenal volume and width of 21OHD patients were significantly larger than those of controls (18.2±12.2 mL vs. 7.1±2.0 mL, 4.7±1.9 mm vs. 3.3±0.5 mm, P<0.001 for both). The 17-OHP and androstenedione levels were highest in patients with adrenal hypertrophy, followed by those with normal adrenal glands and adrenal hypotrophy (P<0.05 for both). Adrenal volume and width correlated positively with adrenocorticotropic hormone, 17-OHP, 11β-hydroxytestosterone, progesterone sulfate, and dehydroepiandrosterone sulfate in both sexes (r=0.33–0.95, P<0.05 for all). For identifying well-controlled patients, the optimal cut-off values of adrenal volume and width were 10.7 mL and 4 mm, respectively (area under the curve, 0.82–0.88; P<0.001 for both).
Conclusion Adrenal volume and width may be reliable quantitative parameters for monitoring patients with classical 21OHD.
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Long‐term health consequences of congenital adrenal hyperplasia Riccardo Pofi, Xiaochen Ji, Nils P. Krone, Jeremy W. Tomlinson Clinical Endocrinology.2023;[Epub] CrossRef
Landscape of Adrenal Tumours in Patients with Congenital Adrenal Hyperplasia Mara Carsote, Ana-Maria Gheorghe, Claudiu Nistor, Alexandra-Ioana Trandafir, Oana-Claudia Sima, Anca-Pati Cucu, Adrian Ciuche, Eugenia Petrova, Adina Ghemigian Biomedicines.2023; 11(11): 3081. CrossRef
Multiplexed Serum Steroid Profiling Reveals Metabolic Signatures of Subtypes in Congenital Adrenal Hyperplasia Jaeyoon Shim, Chang Ho Ahn, Seung Shin Park, Jongsung Noh, Chaelin Lee, Sang Won Lee, Jung Hee Kim, Man Ho Choi Journal of the Endocrine Society.2023;[Epub] CrossRef
Long-Term Outcomes of Congenital Adrenal Hyperplasia Anna Nordenström, Svetlana Lajic, Henrik Falhammar Endocrinology and Metabolism.2022; 37(4): 587. CrossRef
Congenital adrenal hyperplasia in patients with adrenal tumors: a population-based case–control study F. Sahlander, J. Patrova, B. Mannheimer, J. D. Lindh, H. Falhammar Journal of Endocrinological Investigation.2022; 46(3): 559. CrossRef
Fully automatic volume measurement of the adrenal gland on CT using deep learning to classify adrenal hyperplasia Taek Min Kim, Seung Jae Choi, Ji Yeon Ko, Sungwan Kim, Chang Wook Jeong, Jeong Yeon Cho, Sang Youn Kim, Young-Gon Kim European Radiology.2022; 33(6): 4292. CrossRef
Eu Jeong Ku, Chaelin Lee, Jaeyoon Shim, Sihoon Lee, Kyoung-Ah Kim, Sang Wan Kim, Yumie Rhee, Hyo-Jeong Kim, Jung Soo Lim, Choon Hee Chung, Sung Wan Chun, Soon-Jib Yoo, Ohk-Hyun Ryu, Ho Chan Cho, A Ram Hong, Chang Ho Ahn, Jung Hee Kim, Man Ho Choi
Endocrinol Metab. 2021;36(5):1131-1141. Published online October 21, 2021
Background Conventional diagnostic approaches for adrenal tumors require multi-step processes, including imaging studies and dynamic hormone tests. Therefore, this study aimed to discriminate adrenal tumors from a single blood sample based on the combination of liquid chromatography-mass spectrometry (LC-MS) and machine learning algorithms in serum profiling of adrenal steroids.
Methods The LC-MS-based steroid profiling was applied to serum samples obtained from patients with nonfunctioning adenoma (NFA, n=73), Cushing’s syndrome (CS, n=30), and primary aldosteronism (PA, n=40) in a prospective multicenter study of adrenal disease. The decision tree (DT), random forest (RF), and extreme gradient boost (XGBoost) were performed to categorize the subtypes of adrenal tumors.
Results The CS group showed higher serum levels of 11-deoxycortisol than the NFA group, and increased levels of tetrahydrocortisone (THE), 20α-dihydrocortisol, and 6β-hydroxycortisol were found in the PA group. However, the CS group showed lower levels of dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S) than both the NFA and PA groups. Patients with PA expressed higher serum 18-hydroxycortisol and DHEA but lower THE than NFA patients. The balanced accuracies of DT, RF, and XGBoost for classifying each type were 78%, 96%, and 97%, respectively. In receiver operating characteristics (ROC) analysis for CS, XGBoost, and RF showed a significantly greater diagnostic power than the DT. However, in ROC analysis for PA, only RF exhibited better diagnostic performance than DT.
Conclusion The combination of LC-MS-based steroid profiling with machine learning algorithms could be a promising one-step diagnostic approach for the classification of adrenal tumor subtypes.
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Endocrinol Metab. 2021;36(4):875-884. Published online August 11, 2021
Background Adrenal venous sampling (AVS) is performed to distinguish the subtype of primary aldosteronism (PA). The clinical implication of contralateral suppression (CS; aldosterone/cortisolnondominantperipheral) at AVS remains unclear. We aimed to investigate the clinical significance of CS and its impact on postoperative outcomes after unilateral adrenalectomy.
Methods In this retrospective observational multi-center study, we analyzed PA patients who underwent both successful adrenocorticotropin hormone-stimulated AVS and unilateral adrenalectomy. Successful cannulation was defined as the selectivity index (cortisoladrenal/ cortisolperipheral) ≥3. Clinical and biochemical outcomes after unilateral adrenalectomy were evaluated based on the international Primary Aldosteronism Surgical Outcome consensus.
Results Among 263 patients analyzed, 247 had CS (93.9%). Patients with CS had lower serum potassium levels, higher plasma aldosterone concentration, higher aldosterone-to-renin ratio (ARR), and larger adenoma size than those without CS. Those with CS showed significantly higher lateralization index than those without CS (P<0.001). Although postoperative blood pressure and ARR significantly decreased in those with CS, clinical and biochemical outcomes were comparable in both groups. When the cut-off value of age was determined using receiver operating characteristic (ROC) analysis, patients aged ≥50 years old with contralateral suppression index (CSI; the ratio between aldosterone/cortisolnondominant and aldosterone/cortisolperipheral) ≤0.26 had greater odds ratio (6.43; 95% confidence interval, 1.30 to 31.69) of incident chronic kidney disease than those aged <50 years with CSI >0.26 after adjusting for other factors.
Conclusion CS may not predict postoperative clinical and biochemical outcomes in subjects with unilateral aldosterone excess, but it is associated with postsurgical deterioration of renal function in subjects over 50 years with CSI ≤0.26.
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Significant progress in pituitary and adrenal diseases was made in 2020. This review presents major translational and clinical advances in research on pituitary and adrenal diseases, encompassing their epidemiology, pathogenesis, diagnosis, and clinical management. We address the controversy regarding the nomenclature of pituitary neuroendocrine tumors, omics-based molecular classification of pituitary adenomas, and novel drugs for Cushing’s disease in the field of pituitary diseases. In the field of adrenal diseases, we cover big data-driven epidemiology of adrenal tumors, steroid profiling as a new diagnostic tool, and the utility of scoring systems in the decision-making process of managing primary aldosteronism. This brief article will broaden readers’ understanding of pituitary and adrenal diseases.
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Primary aldosteronism (PA) is the most common cause of secondary hypertension, and is associated with an increased incidence of cardiovascular events. PA itself is clinically classified into the following two types: unilateral PA, mostly composed of aldosteroneproducing adenoma (APA); and bilateral hyperaldosteronism, consisting of multiple aldosterone-producing micronodules (APMs) and aldosterone-producing diffuse hyperplasia. Histopathologically, those disorders above are all composed of compact and clear cells. The cellular morphology in the above-mentioned aldosterone-producing disorders has been recently reported to be closely correlated with patterns of somatic mutations of ion channels including KCNJ5, CACNA1D, ATP1A1, ATP2B3, and others. In addition, in non-pathological adrenal glands, APMs are frequently detected regardless of the status of the renin-angiotensin-aldosterone system (RAAS). Aldosterone-producing nodules have been also proposed as non-neoplastic nodules that can be identified by hematoxylin and eosin staining. These non-neoplastic CYP11B2-positive nodules could represent possible precursors of APAs possibly due to the presence of somatic mutations. On the other hand, aging itself also plays a pivotal role in the development of aldosterone-producing lesions. For instance, the number of APMs was also reported to increase with aging. Therefore, recent studies indicated the novel classification of PA into normotensive PA (RAAS-independent APM) and clinically overt PA.
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