Mild autonomous cortisol secretion: pathophysiology, comorbidities and management approaches.

The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1-7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20-50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS.

Aldosterone-producing adenoma-harbouring KCNJ5 mutations is associated with lower prevalence of metabolic disorders and abdominal obesity.

OBJECTIVE: Aldosterone overproduction and lipid metabolic disturbances between idiopathic hyperaldosteronism (IHA) and unilateral aldosterone-producing adenoma (APA) have been inconsistently linked in patients with primary aldosteronism. Moreover, KCNJ5 mutations are prevalent among APAs and enhance aldosterone synthesis in adrenal cortex. We aimed to investigate the prevalence of metabolic syndrome (MetS) in each primary aldosteronism subtype and observe the role of KCNJ5 mutations among APAs on the distribution of abdominal adipose tissues quantified using computed tomography (CT), including their changes postadrenalectomy. DESIGN AND METHODS: We retrospectively collected 244 and 177 patients with IHA and APA at baseline. Patients with APA had undergone adrenalectomy, and gene sequencing revealed the absence (n = 75) and presence (n = 102) of KCNJ5 mutations. We also recruited 31 patients with APA who had undergone CT-scan 1-year postadrenalectomy. RESULTS: The patients with APA harbouring KCNJ5 mutations had significantly lower prevalence of MetS and smaller distribution in waist circumference, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) than the other groups. Logistic regression analysis indicated that the VAT area correlated significantly with KCNJ5 mutations among the APAs. Only participants with KCNJ5 mutations had significant increases in triglycerides, cholesterol, SAT, and VAT after 1-year postadrenalectomy. CONCLUSION: This study is the first to demonstrate that MetS and abdominal obesity were less prevalent in the patients with APA harbouring KCNJ5 mutations compared with the IHA group and the non-KCNJ5-mutated APA group. Increasing prevalence of dyslipidaemia and abdominal obesity was observed in patients with KCNJ5 mutations 1-year postadrenalectomy.

Cardiovascular and metabolic consequences in patients with asymptomatic adrenal adenomas.

PURPOSE OF REVIEW: The incidence of adrenal tumors has increased over the past 20 years, most of which are incidentally discovered nonfunctioning adenomas (NFA) and tumors with mild autonomous cortisol secretion (MACS). This review aimed to summarize recent progress in understanding cardiometabolic risk in patients with NFA and MACS and to provide updates on the effect of treatment on improving outcomes in this population. RECENT FINDINGS: NFA and MACS are associated with adverse cardiovascular risk factors and metabolic derangements, which are likely mediated by excessive glucocorticoid secretion. Recent studies showed significantly higher prevalence of hypertension, impaired glucose metabolism, obesity, and dyslipidemia in patients with NFA and MACS. Adrenalectomy may improve comorbidities in selected patients. SUMMARY: Asymptomatic adrenal adenomas are common and are associated with adverse cardiometabolic changes. In selected patients, adrenalectomy may reduce cardiometabolic risk and improve clinical outcomes.

Aldosterone is Aberrantly Regulated by Various Stimuli in a High Proportion of Patients with Primary Aldosteronism.

CONTEXT: In primary aldosteronism (PA), aldosterone secretion is relatively independent of the renin-angiotensin system, but can be regulated by several other stimuli. OBJECTIVE: To evaluate aldosterone response to several stimuli in a series of patients with PA secondary either to bilateral adrenal hyperplasia (BAH) or unilateral aldosterone-producing adenoma (APA). DESIGN AND SETTING: Prospective cohort study conducted in a university teaching hospital research center. PATIENTS: Forty-three patients with confirmed PA and subtyped by adrenal vein sampling (n = 39) were studied, including 11 with BAH, 28 with APA, and 4 with undefined etiology. We also studied 4 other patients with aldosterone and cortisol cosecretion. INTERVENTIONS: We systematically explored aberrant regulation of aldosterone using an in vivo protocol that included the following stimulation tests performed over 3 days under dexamethasone suppression: upright posture, mixed meal, adrenocorticotropin (ACTH) 1-24, gonadotropin-releasing hormone (GnRH), vasopressin, and serotonin R4 agonist. MAIN OUTCOME MEASURES: Positive response was defined as >50% renin or ACTH-independent increase in plasma aldosterone/cortisol concentration following the various stimulation tests. RESULTS: Renin-independent aldosterone secretion increased in response to several aberrant stimuli (upright posture, GnRH) in up to 83% of patients with APA or BAH in whom ACTH 1-24 and HT4R agonists also produced aldosterone oversecretion in all patients. The mean significant aberrant responses per patient was similar in BAH (4.6) and in APA (4.0). CONCLUSIONS: Aldosterone secretion in PA is relatively autonomous from the renin-angiotensin system, but is highly regulated by several other stimuli, which contributes to the large variability of aldosterone levels in PA patients.

Epidemiology and Comorbidity of Adrenal Cushing Syndrome: A Nationwide Cohort Study.

CONTEXT: Adrenal Cushing syndrome (CS) is a major subtype of CS and has a high surgical cure rate. However, only a few studies have investigated the epidemiology and long-term outcomes of adrenal CS. OBJECTIVE: We aimed to investigate the nationwide epidemiology, long-term prognosis, and postoperative glucocorticoid replacement therapies of adrenal CS in Korea. DESIGN: Retrospective cohort study. SETTING: A nationwide claim database. PATIENTS: Adrenal CS patients who were defined as having undergone adrenalectomy, a diagnosis code of CS, and not having pituitary gland surgery. MAIN OUTCOME MEASURES: Crude incidence and age-standardized incidence rates, long-term mortality, comorbidities diagnosed preoperatively or developed postoperatively, and the pattern of postoperative glucocorticoid replacement therapy. RESULTS: From 2002 to 2017, there were a total of 1199 new adrenal CS patients, including 72 patients with adrenocortical carcinoma (malignant adrenal CS), in Korea. The crude and age-standardized incidence rates were 1.51 and 1.27 per million person-years, respectively. The overall standardized mortality ratio was 3.0 (95% confidence interval [CI], 2.4-3.7) for benign adrenal CS and 13.1 (95% CI, 7.6-18.6) for malignant adrenal CS. Adrenal CS patients had a high risk of having coronary artery disease, stroke, metabolic diseases, and depression. A similar proportion of patients were diagnosed with these comorbidities both preoperatively and postoperatively, suggesting a significant residual risk even after adrenalectomy. The median time of postoperative glucocorticoid replacement therapy was 10.1 months, and the major types of glucocorticoids used were prednisolone (66.6%) and hydrocortisone (22.4%). CONCLUSIONS: Adrenal CS is associated with multiple comorbidities even after treatment, which necessitates meticulous postoperative care.

RNA Sequencing and Somatic Mutation Status of Adrenocortical Tumors: Novel Pathogenetic Insights.

CONTEXT: Pathogenesis of autonomous steroid secretion and adrenocortical tumorigenesis remains partially obscure. OBJECTIVE: To investigate the relationship between transcriptome profile and genetic background in a large series of adrenocortical tumors and identify new potential pathogenetic mechanisms. DESIGN: Cross-sectional study. SETTING: University Hospitals of the European Network for the Study of Adrenal Tumors (ENSAT). PATIENTS: We collected snap-frozen tissue from patients with adrenocortical tumors (n = 59) with known genetic background: 26 adenomas with Cushing syndrome (CS- cortisol-producing adenoma [CPA]), 17 adenomas with mild autonomous cortisol secretion (MACS-CPAs), 9 endocrine-inactive adenomas (EIAs), and 7 adrenocortical carcinomas (ACCs). INTERVENTION: Ribonucleic acid (RNA) sequencing. MAIN OUTCOME MEASURES: Gene expression, long noncoding RNA (lncRNA) expression, and gene fusions. Correlation with genetic background defined by targeted Sanger sequencing, targeted panel- or whole-exome sequencing. RESULTS: Transcriptome analysis identified 2 major clusters for adenomas: Cluster 1 (n = 32) mainly consisting of MACS-CPAs with CTNNB1 or without identified driver mutations (46.9% of cases) and 8/9 EIAs; Cluster 2 (n = 18) that comprised CP-CPAs with or without identified driver mutation in 83.3% of cases (including all CS-CPAs with PRKACA mutation). Two CS-CPAs, 1 with CTNNB1 and 1 with GNAS mutation, clustered separately and relatively close to ACC. lncRNA analysis well differentiate adenomas from ACCs. Novel gene fusions were found, including AKAP13-PDE8A in one CS-CPA sample with no driver mutation. CONCLUSIONS: MACS-CPAs and EIAs showed a similar transcriptome profile, independently of the genetic background, whereas most CS-CPAs clustered together. Still unrevealed molecular alterations in the cAMP/PKA or Wnt/beta catenin pathways might be involved in the pathogenesis of adrenocortical tumors.

Basal contralateral aldosterone suppression is rare in lateralized primary aldosteronism.

CONTEXT: Unilateral aldosteronomas should suppress renin and contralateral aldosterone secretion. Complete aldosterone suppression in contralateral adrenal vein sample (AVS) could predict surgical outcomes. OBJECTIVES: To retrospectively evaluate the prevalence of basal contralateral suppression using Aldosterone (A)contralateral(CL)/Aperipheral(P) as compared to (A/Cortisol(C)CL)/(A/C)P ratio in primary aldosteronism (PA) patients studied in two Canadian centers. To determine the best cut-off to predict clinical and biochemical surgical cure. To compare the accuracy of ACL/AP to the basal and post-ACTH lateralization index (LI) in predicting surgical cure. METHODS: In total, 330 patients with PA and successful AVS were included; 124 lateralizing patients underwent surgery. Clinical and biochemical cure at 3 and 12 months were evaluated using the PASO criteria. RESULTS: Using ACL/AP and (A/C)CL/(A/C)P at the cut-off of 1, the prevalence of contralateral suppression was 6 and 45%, respectively. Using ROC curves, the ACL/AP ratio is associated with clinical cure at 3 and 12 months and biochemical cure at 12 months. (A/C)CL/(A/C)P is associated with biochemical cure only. The cut-offs for ACL/AP offering the best sensitivity (Se) and specificity (Sp) for clinical and biochemical cures at 12 months are 2.15 (Se: 63% and Sp: 71%) and 6.15 (Se: 84% and Sp: 77%), respectively. Basal LI and post-ACTH LI are associated with clinical cure but only the post-ACTH LI is associated with biochemical cure. CONCLUSIONS: In lateralized PA, basal contralateral suppression defined by ACL/AP is rare and incomplete compared to the (A/C)CL/(A/C)P ratio and is associated with clinical and biochemical postoperative outcome, but with modest accuracy.

Frailty in Patients With Mild Autonomous Cortisol Secretion is Higher Than in Patients with Nonfunctioning Adrenal Tumors.

CONTEXT: Mild autonomous cortisol secretion (MACS) affects up to 50% of patients with adrenal adenomas. Frailty is a syndrome characterized by the loss of physiological reserves and an increase in vulnerability, and it serves as a marker of declining health. OBJECTIVE: To compare frailty in patients with MACS versus patients with nonfunctioning adrenal tumors (NFAT). DESIGN: Retrospective study, 2003-2018. SETTING: Referral center. PATIENTS: Patients >20 years of age with adrenal adenoma and MACS (1 mg overnight dexamethasone suppression (DST) of 1.9-5 µg/dL) and NFAT (DST <1.9 µg/dL). MAIN OUTCOME MEASURE: Frailty index (range 0-1), calculated using a 47-variable deficit model. RESULTS: Patients with MACS (n = 168) demonstrated a higher age-, sex-, and body mass index-adjusted prevalence of hypertension (71% vs 60%), cardiac arrhythmias (50% vs 40%), and chronic kidney disease (25% vs 17%), but a lower prevalence of asthma (5% vs 14%) than patients with NFAT (n = 275). Patients with MACS reported more symptoms of weakness (21% vs 11%), falls (7% vs 2%), and sleep difficulty (26% vs 15%) as compared with NFAT. Age-, sex- and BMI-adjusted frailty index was higher in patients with MACS vs patients with NFAT (0.17 vs 0.15; P = 0.009). Using a frailty index cutoff of 0.25, 24% of patients with MACS were frail, versus 18% of patients with NFAT (P = 0.028). CONCLUSION: Patients with MACS exhibit a greater burden of comorbid conditions, adverse symptoms, and frailty than patients with NFAT. Future prospective studies are needed to further characterize frailty, examine its responsiveness to adrenalectomy, and assess its influence on health outcomes in patients with MACS.

Hypokalemia and the Prevalence of Primary Aldosteronism.

Hypokalemia is closely linked with the pathophysiology of primary aldosteronism (PA). Although hypokalemic PA is less common than the normokalemic course of the disease, hypokalemia is of particular importance for the manifestation and development of comorbidities. Specifically, a growing body of evidence demonstrates that hypokalemia in PA patients is associated with a more severe disease course regarding cardiovascular and metabolic morbidity and mortality. It is also well appreciated that low potassium levels per se can promote or exacerbate hypertension. The spectrum of hypokalemia-related symptoms ranges from asymptomatic courses to life-threatening conditions. Hypokalemia is found in 9-37% of all cases of PA with a predominance in patients with aldosterone producing adenoma. Conversely, hypokalemia resolves in almost 100% of cases after both, specific medical or surgical treatment of the disease. However, to date, high-level evidence about the prevalence of primary aldosteronism in a hypokalemic population is missing. Epidemiological data are expected from the recently launched IPAHK+study ("Incidence of Primary Aldosteronism in Patients with Hypokalemia").

Prevalence, diagnosis and outcomes of treatment for primary aldosteronism.

Primary aldosteronism (PA) is the most common potentially curable form of hypertension. The overproduction of aldosterone leads to an increased risk of cardiovascular and cerebrovascular events as well as adverse effects to the heart and kidney and psychological disorders. PA is mainly caused by unilateral aldosterone excess due to an aldosterone-producing adenoma or bilateral excess due to bilateral adrenocortical hyperplasia. The diagnostic work-up of PA comprises three steps: screening, confirmatory testing and differentiation of unilateral surgically-correctable forms from medically treated bilateral PA. These specific treatments can mitigate or reverse the increased risks associated with PA. Herein we summarise the prevalence, outcomes and current and future clinical approaches for the diagnosis of primary aldosteronism.

A nationwide survey of adrenal incidentalomas in Japan: the first report of clinical and epidemiological features.

The aim of this study was to reveal clear epidemiologic and clinical characteristics of incidentally discovered adrenal masses, termed adrenal incidentalomas (AIs), and to establish appropriate managemental and therapeutic regimens in Japan. This study had been originally carried out as a project of a research proposed on behalf of the Japanese Ministry of Health, Labour and Welfare, from 1999 to 2004. This nationwide multicenter study on AIs included 3,672 cases with clinically diagnosed AIs, involving 1,874 males and 1,738 females, with mean age 58.1 ± 13.0 years (mean ± SD). In the present study, we focused on the investigation of the real prevalence of various adrenal disorders with AI. The mean nodule size of AI based on computed tomography was 3.0 ± 2.0 cm. Compared to non-functioning adenomas (NFAs), tumor diameters were significantly larger in adrenocortical carcinomas (ACCs), pheochromocytomas, cortisol-producing adenomas (CPAs), myelolipomas, metastatic tumors, cysts, and ganglioneuromas (p < 0.01). Endocrinological evaluations demonstrated that 50.8% of total AIs were non-functioning adenomas, while 10.5%, including 3.6% with subclinical Cushing's syndrome, were reported as CPAs, 8.5% as pheochromocytomas, and 5.1% as aldosterone-producing adenomas. ACCs were accounted for 1.4% (50 cases) among our series of AIs. In conclusion, while almost 50 % of AIs are non-functional adenomas, we must be particularly careful as AIs include pheochromocytomas or adrenal carcinomas, because they may be asymptomatic. To our knowledge, this is the first and the largest investigation of AI, thus providing basic information for the establishment of clinical guidelines for the management of AI.

Risk of new-onset autoimmune diseases in primary aldosteronism: a nation-wide population-based study.

OBJECTIVE: The association between hyperaldosteronism and autoimmune disorders has been postulated. However, long-term incidence of a variety of new-onset autoimmune diseases (NOAD) among patients with primary aldosteronism has not been well investigated. METHODS: From Taiwan's National Health Insurance Research Database with a 23-million population insurance registry, the identification of primary aldosteronism, essential hypertension and NOAD as well as all-cause mortality were ascertained by a validated algorithm. RESULTS: From 1997 to 2009, 2319 primary aldosteronism patients without previously autoimmune disease were identified and propensity score-matched with 9276 patients with essential hypertension. Among those primary aldosteronism patients, 806 patients with aldosterone-producing adenomas (APA) were identified and matched with 3224 essential hypertension controls. NOAD incidence is augmented in primary aldosteronism patients compared with its matched essential hypertension (hazard ratio 3.82, P < 0.001, versus essential hypertension). Furthermore, NOAD incidence is also higher in APA patients compared with its matched essential hypertension (hazard ratio = 2.96, P < 0.001, versus essential hypertension). However, after a mean 8.9 years of follow-up, primary aldosteronism patients who underwent adrenalectomy (hazard ratio = 3.10, P < 0.001, versus essential hypertension) and took mineralocorticoid receptor antagonist (MRA) still had increased NOAD incidence (hazard ratio = 4.04, P < 0.001, versus essential hypertension). CONCLUSION: Primary aldosteronism patients had an augmented risk for a variety of incident NOAD and all-cause of mortality, compared with matched essential hypertension controls. Notably, the risk of incident NOAD remained increased in patients treated by adrenalectomy or MRA compared with matched essential hypertension controls. This observation supports the theory of primary aldosteronism being associated with a higher risk of multiple autoimmune diseases.

Modern Management of Mild Autonomous Cortisol Secretion.

Incidentally discovered adrenal tumors are reported in ~ 5% of adults undergoing cross-sectional imaging. Mild autonomous cortisol secretion (MACS) from the adrenal mass is demonstrated in 5-48% of patients with adrenal tumors. The diagnosis of MACS represents a challenge due to limitations of the currently used diagnostic tests, differences in the definitions of the clinically relevant MACS, and heterogeneity in an individual's susceptibility to abnormal cortisol secretion from the adrenal mass. Patients with MACS present with increased risk of cardiovascular risk factors, cardiovascular events, metabolic bone disease, and mortality. Adrenalectomy improves or reverses MACS-associated comorbidities in selected patients. The current review will address diagnostic and management challenges in the care of patients with MACS, discuss data on emerging biomarkers, and suggest future directions in the field of MACS.

Unanswered Questions in the Genetic Basis of Primary Aldosteronism.

Over the past six years, the genetic basis of a significant fraction of primary aldosteronism (PA) cases has been solved. Breakthrough discoveries include the role of somatic variants in the KCNJ5, CACNA1D, ATP1A1, and ATP2B3 genes as causes of aldosterone-producing adenomas (APAs), and the recognition of three novel hyperaldosteronism syndromes with germline variants in the KCNJ5, CACNA1D, and CACNA1H genes. The description of somatic variants in CACNA1D and ATP1A1 in aldosterone-producing cell clusters (APCCs) suggests that these clusters are precursors of some aldosterone-producing adenomas. Yet, a number of questions remain unanswered. These include the genetic basis of about 40% of APAs without somatic variants in known genes. Do technical issues explain this finding, or are the unexplained APAs due to somatic copy number variation or rare variants in thus-far undiscovered genes? Similarly, the role of CTNNB1 (beta catenin) variants in APA pathogenesis is still unclear. The major question to be solved is the genetic basis of bilateral adrenal hyperplasia (BAH). Is BAH due to the bilateral occurrence of APCCs, to germline variants, or perhaps due to unknown serum factors? Lastly, the etiology of unsolved cases of apparently familial hyperaldosteronism remains to be discovered. It is expected that genetic studies over the next few years will lead to answers to at least some of the questions raised.

Biochemical and clinical benefits of unilateral adrenalectomy in patients with subclinical hypercortisolism and bilateral adrenal incidentalomas.

OBJECTIVE: The treatment of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas (AI) is debatable. We aimed to compare the biochemical and clinical outcome of unilateral adrenalectomy vs a conservative approach in these patients. DESIGN: Retrospective study. METHODS: The study included 33 patients with bilateral AI; 14 patients underwent unilateral adrenalectomy of the largest lesion (surgical group), whereas 19 patients were followed up (follow-up group). At baseline and at each follow-up visit, we measured 0800 h plasma ACTH, midnight serum cortisol (MSF), 24-h urinary-free cortisol (UFC) and serum cortisol following a standard 2-day low-dose-dexamethasone-suppression test (LDDST). We evaluated the following comorbidities: arterial hypertension, impaired glucose tolerance or diabetes mellitus, dyslipidemia and osteoporosis. RESULTS: Baseline demographic, clinical characteristics and the duration of follow-up (53.9±21.3 vs 51.8±20.1 months, for the surgical vs the follow-up group) were similar between groups. At the last follow-up visit the surgical group had a significant reduction in post-LDDST cortisol (2.4±1.6 vs 6.7±3.9 µg/dl, P=0.002), MSF (4.3±2 vs 8.8±4.6 µg/dl, P=0.006) and 24-h UFC (50.1±21.1 vs 117.9±42.4 µg/24 h, P=0.0007) and a significant rise in mean±s.d. morning plasma ACTH levels (22.2±9.6 vs 6.9±4.8 pg/ml, P=0.002). Improvement in co-morbidities was seen only in the surgical group, whereas no changes were noted in the follow-up group. CONCLUSIONS: Our early results show that removal of the largest lesion offers significant improvement both to cortisol excess and its metabolic consequences, without the debilitating effects of bilateral adrenalectomy. A larger number of patients, as well as a longer follow-up, are required before drawing solid conclusions.

Adrenal steroidogenesis and congenital adrenal hyperplasia.

Adrenal steroidogenesis is a dynamic process, reliant on de novo synthesis from cholesterol, under the stimulation of ACTH and other regulators. The syntheses of mineralocorticoids (primarily aldosterone), glucocorticoids (primarily cortisol), and adrenal androgens (primarily dehydroepiandrosterone and its sulfate) occur in separate adrenal cortical zones, each expressing specific enzymes. Congenital adrenal hyperplasia (CAH) encompasses a group of autosomal-recessive enzymatic defects in cortisol biosynthesis. 21-Hydroxylase (21OHD) deficiency accounts for more than 90% of CAH cases and, when milder or nonclassic forms are included, 21OHD is one of the most common genetic diseases.

Adrenal mild hypercortisolism.

Adrenal incidentalomas have become detected more often as the use of abdominal imaging has increased. Up to one-third of these may be secreting low levels of cortisol, known as mild hypercortisolism or subclinical Cushing syndrome. These low levels of cortisol have been found to be associated with an increased in the metabolic syndrome, osteoporosis, cardiovascular events, and mortality. This article discusses in detail the epidemiology, diagnosis, clinical associations, and treatment options of mild hypercortisolism.

Adrenal adenomas, subclinical hypercortisolism, and cardiovascular outcomes.

PURPOSE OF REVIEW: Recent evidence has highlighted the link between cardiovascular outcomes and incidentally discovered adrenal masses. The purpose of this review is to summarize the most recent findings on the cardiovascular profile of patients with nonfunctional adrenal adenomas. RECENT FINDINGS: Nonsecreting adrenal tumors, defined mostly by cortisol levels after dexamethasone suppression test below 1.8 µg/dl, are associated with impairment of markers of subclinical atherosclerosis such as intima-media thickness and flow-mediated vasodilation. The presence of impaired indices of insulin resistance could represent an additional factor that contributes to the worsening of the cardiovascular profile of those patients. No evidence of increased cardiovascular outcomes was found in this group of patients. On the contrary, according to the findings of recent long-term retrospective studies, patients with subclinical hypercortisolism have an increased incidence of cardiovascular outcomes and related mortality with respect to nonsecreting adrenal masses and to the general population. SUMMARY: An impaired cardiovascular profile is a common finding in patients with apparently nonfunctional adrenal masses. However, the incidence of cardiovascular outcomes and related mortality seems to be increased only in patients with mild cortisol hypersecretion.

Computed tomography criteria for discrimination of adrenal adenomas and adrenocortical carcinomas: analysis of the German ACC registry.

OBJECTIVE: Thresholds of 2-20 hounsfield units (HU) in unenhanced computed tomography (CT) are suggested to discriminate benign adrenal tumors (BATs) from malignant adrenal tumors. However, these studies included only low numbers of adrenocortical carcinomas (ACCs). This study defines a HU threshold by inclusion of a large cohort of ACCs. DESIGN: Retrospective, blinded, comparative analysis of CT scans from 51 patients with ACCs (30 females, median age 49 years) and 25 patients with BATs (12 females, median age 64 years) diagnosed during the period of 2005-2010 was performed. METHODS: Tumor density was evaluated in unenhanced CT by two blinded investigators. RESULTS: Median tumor size was 9 cm (range 2.0-20) for ACCs vs 4 cm (2.0-7.5) for BATs (P<0.0001). In ACCs, the median unenhanced HU value was 34 (range 14-74) in comparison with 5 (-13 to 40) in BATs (P<0.0001). ROC analysis revealed a HU of 21 as threshold with the best diagnostic accuracy (sensitivity 96%, specificity 80%, and AUC 0.89). However, two ACCs that were 5 and 6 cm in size would have been missed. Setting the threshold to 13.9 allowed for 100% sensitivity, but a lower specificity of 68%. CONCLUSIONS: This first large study on ACCs confirmed that the vast majority of ACCs have unenhanced HU >21. However, to avoid misdiagnosing an ACC as benign, a threshold of 13 should be used.

Changes in the clinical manifestations of primary aldosteronism.

BACKGROUND/AIMS: Primary aldosteronism (PA) is now widely recognized to have a higher prevalence than was once thought. In view of its increasing prevalence, we compared chronological changes in clinical manifestations of PA according to different times of diagnosis. METHODS: In total, 85 patients diagnosed with PA from January 1986 through March 2012 were reviewed retrospectively, based on their medical records. During two periods-1986 to 2005 and 2006 to 2012-41 and 44 patients, respectively, were diagnosed with PA. We compared the clinical and biological characteristics of PA between these periods. RESULTS: The results demonstrate an increasing trend in the prevalence of idiopathic hyperaldosteronism (IHA; p = 0.19). In the 2006 to 2012 period, patients with PA presented with higher serum potassium levels at the time of diagnosis than in the 1986 to 2005 period (p < 0.0002). Adrenal vein sampling (AVS) was performed mostly in the latter period (82.3%) and the diagnostic accuracy of adrenal computed tomography, compared with AVS, was only 56.2%. About 78.0% versus 86.3% of patients had at least one target organ damage (TOD) in the 1986 to 2005 and 2006 to 2012 periods, respectively (p = 0.39). However, patients with TOD were older and had longer durations of hypertension than patients without, in both periods. CONCLUSIONS: PA is becoming more prevalent. There was an increasing tendency for IHA, and more PA patients presented with normokalemia than in the earlier period. Early and accurate diagnosis of PA with AVS and proper treatment should have substantial prognostic value.