Approach to the Patient with Bilateral Adrenal Masses.

Bilateral adrenal masses, increasingly encountered in clinical practice, manifest across diverse contexts, including incidental discovery, malignancy staging, and targeted imaging after hormonal diagnosis of adrenal disorders. The spectrum encompasses various pathologies, such as cortical adenomas, macronodular adrenal disease, pheochromocytomas, myelolipomas, infiltrative disorders, primary and secondary malignancies. Notably, not all masses in both adrenal glands necessarily share the same etiology, often exhibiting diverse causes. Recently, the European Society of Endocrinology and the European Network for the Study of Adrenal Tumors updated guidelines, introduced a four-option schema based on imaging, aiding in targeted hormonal testing and management. This "Approach to the Patient" review delves into the latest advancements in imaging, biochemical and, genetic approaches for the diagnostic and management nuances of bilateral adrenal masses. It provides insights and a contemporary framework for navigating the complexities associated with this clinical entity.

The Role of Somatostatin Analogues in the Control of Diarrhea and Flushing as Markers of Carcinoid Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Somatostatin analogues (SSAs) are the cornerstone of treatment for carcinoid syndrome (CS)-related symptoms. The aim of this systematic review and meta-analysis is to evaluate the percentage of patients achieving partial (PR) or complete response (CR) with the use of long-acting SSAs in patients with CS. METHODS: A systematic electronic literature search was conducted in PubMed, Cochrane, and Scopus to identify eligible studies. Any clinical trials reporting data on the efficacy of SSAs to alleviate symptoms in adult patients were considered as potentially eligible. RESULTS: A total of 17 studies reported extractable outcomes (PR/CR) for quantitative synthesis. The pooled percentage of patients with PR/CR for diarrhea was estimated to be 0.67 (95% confidence interval (CI): 0.52-0.79, I2 = 83%). Subgroup analyses of specific drugs provided no evidence of a differential response. With regards to flushing, the pooled percentage of patients with PR/CR was estimated to be 0.68 (95% CI: 0.52-0.81, I2 = 86%). Similarly, no evidence of a significant differential response in flushing control was documented. CONCLUSIONS: We estimate there is a 67-68% overall reduction in symptoms of CS associated with SSA treatment. However, significant heterogeneity was detected, possibly revealing differences in the disease course, in management and in outcome definition.

Diagnostic workup of Cushing's syndrome.

Cushing's syndrome (CS) is a rare but detrimental endocrine disorder. Early diagnosis and prompt treatment are essential since the duration of hypercortisolism has an adverse impact on the extent of comorbidities and overall survival. The diagnostic approach involves a stepwise process that includes (1) screening and confirming the diagnosis and (2) establishing the aetiology of CS. The tests currently used to confirm the diagnosis of CS include urinary free cortisol measurements, the dexamethasone suppression test and late- night salivary cortisol or midnight serum cortisol measurements. None of these tests are ideal; all have pitfalls and require careful interpretation. Following confirmation of CS, measurement of ACTH discriminates between ACTH-dependent and non-ACTH dependent causes of CS. Adrenal imaging provides clues for the aetiology of non-ACTH dependent forms. Differentiation between the ACTH-dependent forms that involve pituitary corticotroph adenomas and ectopic ACTH sources is more complex and include pituitary MRI imaging, the high dose dexamethasone suppression test, the CRH test, bilateral inferior petrosal sinus sampling and, when required imaging modalities to detect ectopic ACTH secreting lesions. This review, which is part of a special issue on "Update of Cushing's syndrome: 100 years after Minnie G" will provide an update on our current diagnostic workup for the confirmation and differential diagnosis of CS.

Current approach of primary bilateral adrenal hyperplasia.

PURPOSE OF REVIEW: To discuss the most recent findings on the pathophysiology, the genetic and molecular causes of primary bilateral adrenal hyperplasia (PBAH). The diagnostic approach of patients with PBAH will also be presented in detail with an emphasis on the emerging diagnostic tools and finally, the treatment of PBAH will be discussed with an emphasis on the newest surgical and medical treatment approaches. RECENT FINDINGS: PBAH is a highly heterogeneous condition mostly detected incidentally on abdominal imaging. Based on the size of the nodules, PBAH is subdivided into primary bilateral macronodular adrenal hyperplasia (PBMAH) and micronodular adrenal hyperplasia. A substantial proportion of patients with PBMAH harbor a germline mutation of the armadillo repeat containing 5 tumor suppression gene and therefore genetic testing is strongly recommended. Measurements of plasma or urinary multisteroid profiles show promising results in that PBMAH has a distinctive plasma steroid fingerprint that can help in diagnosis and subtyping of PBMAH. Finally, although surgery is the mainstay of treatment of patients with PBAH, medical therapy is increasingly emerging as an alternative option. SUMMARY: PBAH is a poorly studied and therefore a challenging disease to diagnose and treat. Hopefully with these newest diagnostic and therapeutic tools, a more comprehensive approach will be adopted.

Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study.

BACKGROUND: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). METHODS: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. FINDINGS: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). INTERPRETATION: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. FUNDING: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino.

Cushing's disease: risk of recurrence following trans-sphenoidal surgery, timing and methods for evaluation.

The treatment of choice for Cushing's disease (CD) is trans-sphenoidal surgery (TSS). However, TSS is not always curative and, even when curative it is associated with a substantial rate of recurrence. Published recurrence rates vary between 5 and 20%; half of these recurrences appear within 5-years and the remaining half within or even after 10 years post-surgery. A low or undetectable cortisol in the immediate post-op period is regarded as the best criterion of remission. However, low post-op cortisol levels do not accurately predict long-term remission. Moreover, there are no other robust predictors providing certainty about the long-term outcomes. Interestingly, several studies have shown that the desmopressin test performed in the early post-op period may have some promise in predicting more precisely the risk of recurrence. In view of the lack of robust ways to predict long-term outcomes, current guidelines suggest that every patient in remission should be monitored for the possibility of recurrence. The methods used to detect recurrence are similar to those used to assess the cortisol secretory status and include assessment of: (i) abnormal circadian rhythm by late night salivary cortisol (LNSC) or midnight serum cortisol; (ii) impaired cortisol feedback by the dexamethasone suppression test and; (iii) increased 24-h bioavailable cortisol by urinary free cortisol. The timing of evaluation begins when HPA axis recovers, and then annually or sooner in case of clinical suspicion. Currently LNSC is regarded as the earliest and most sensitive biochemical alteration in detecting recurrence; a major caveat for LNSC, however, is its great variability. In practice, the diagnosis of recurrence is a challenge due to the fact that recurrence is usually a slow process with apparent clinical manifestations that may be delayed and alterations of classical biomarkers that may be delayed as well.

Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study.

BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Loss of KDM1A in GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome: a multicentre, retrospective, cohort study.

BACKGROUND: GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome is caused by aberrant expression of the GIP receptor in adrenal lesions. The bilateral nature of this disease suggests germline genetic predisposition. We aimed to identify the genetic driver event responsible for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. METHODS: We conducted a multicentre, retrospective, cohort study at endocrine hospitals and university hospitals in France, Canada, Italy, Greece, Belgium, and the Netherlands. We collected blood and adrenal samples from patients who had undergone unilateral or bilateral adrenalectomy for GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome. Adrenal samples from patients with primary bilateral macronodular adrenal hyperplasia who had undergone an adrenalectomy for overt or mild Cushing's syndrome without evidence of food-dependent cortisol production and those with GIP-dependent unilateral adrenocortical adenomas were used as control groups. We performed whole genome, whole exome, and targeted next generation sequencing, and copy number analyses of blood and adrenal DNA from patients with familial or sporadic disease. We performed RNA sequencing on adrenal samples and functional analyses of the identified genetic defect in the human adrenocortical cell line H295R. FINDINGS: 17 patients with GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome were studied. The median age of patients was 43·3 (95% CI 38·8-47·8) years and most patients (15 [88%]) were women. We identified germline heterozygous pathogenic or most likely pathogenic variants in the KDM1A gene in all 17 patients. We also identified a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in adrenal lesions of these patients. None of the 29 patients in the control groups had KDM1A germline or somatic alterations. Concomitant genetic inactivation of both KDM1A alleles resulted in loss of KDM1A expression in adrenal lesions. Global gene expression analysis showed GIP receptor upregulation with a log2 fold change of 7·99 (95% CI 7·34-8·66; p=4·4 × 10-125), and differential regulation of several other G protein-coupled receptors in GIP-dependent primary bilateral macronodular hyperplasia samples compared with control samples. In vitro pharmacological inhibition and inactivation of KDM1A by CRISPR-Cas9 genome editing resulted in an increase of GIP receptor transcripts and protein in human adrenocortical H295R cells. INTERPRETATION: We propose that GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndrome results from a two-hit inactivation of KDM1A, consistent with the tumour suppressor gene model of tumorigenesis. Genetic testing and counselling should be offered to these patients and their relatives. FUNDING: Agence Nationale de la Recherche, Fondation du Grand défi Pierre Lavoie, and the French National Cancer Institute.

Long-term outcome of differentiated thyroid cancer in children and young adults: risk stratification by ATA criteria and assessment of pre-ablation stimulated thyroglobulin as predictors of disease persistence.

PURPOSE: Differentiated thyroid cancer (DTC) has an increasing incidence in childhood and adolescence but long-term outcome data are limited. We aimed to identify possible risk factors associated with disease persistence, with special focus on the usefulness of ATA risk stratification system and pre-ablation stimulated thyroglobulin (Tg) levels. METHODS: We retrospectively studied 103 patients, 79 females (76.7%), aged 15.6 ± 3.2 years (range 5-21 years) who underwent total thyroidectomy for DTC. Patients were classified by ATA risk stratification criteria as low, intermediate, and high risk for recurrence. All, except five with papillary microcarcinoma, received radioactive iodine (RAI) treatment. RESULTS: At diagnosis, 44.7% of patients had cervical lymph node and 7.8% pulmonary metastases. Amongst the 72 patients with long-term follow-up data, 31.9% had persistent disease. Lymph node as well as pulmonary metastases and increased pre-ablation stimulated thyroglobulin (Tg) levels were associated with persistent disease. The risk of persistent disease was significantly higher in both the intermediate- (OR 17.95; 95% CI 2.66-120.94, p < 0.01) and high-risk (OR 17.65; 95% CI 4.47-69.74, p < 0.001) groups. ROC curve analysis showed that a pre-ablation Tg level higher than 14 ng/ml had a sensitivity of 94.7% to predict persistence, corresponding to a positive (PPV) and negative predictive values (NPV) of 66.7% and 93.8%, respectively. CONCLUSIONS: ATA risk stratification was validated in our population of children and young adults with DTC. Moreover, pre-ablation stimulated Tg levels of <14 ng/ml were associated with a low risk of long-term persistence and may therefore serve as a marker to identify patients who may need less intensive surveillance.

Approach to patients with bilateral adrenal incidentalomas.

PURPOSE OF REVIEW: The current review provides a summary on the most recent developments regarding the cause, work-up and management of bilateral adrenal incidentalomas (BAI). RECENT FINDINGS: The recent ENS@T/ESE guidelines provide comprehensive directions on the evaluation and management of patients with adrenal incidentalomas with special focus on those with bilateral tumours. Intraadrenal ACTH synthesis that may locally stimulate cortisol secretion challenging the traditionally used term 'ACTH-independent'. Inactivating mutations of a new tumour suppressor gene, armadillo repeat containing 5 (ARMC5), are implicated in a number of patients, especially those with multiple macronodules (bilateral macronodular hyperplasia) and evidence of hypercortisolism. Loss-of-function mutations of the glucocorticoid receptor gene (NR3C1) consist a new possible genetic cause of BAIs. Regarding management an increasing number of studies provide data on the benefits and safety of unilateral rather than bilateral adrenalectomy. There is also emerging data on the beneficial use of steroidogenesis inhibitors in a dosing schedule that aims to mimic the normal cortisol rhythm with promising short-term results, but the long-term clinical benefits of this approach remain to be demonstrated. SUMMARY: The diagnostic approach consists of imaging and hormonal evaluation. Imaging characterization should be done separately for each lesion. Hormonal evaluation includes testing for primary aldosteronism, pheochromocytoma and evaluation for autonomous cortisol secretion, using the 1-mg overnight dexamethasone suppression test. Midnight cortisol or 24-h urinary-free cortisol may aid in establishing the degree of cortisol excess. In patients with hypercortisolism ACTH levels should be measured to establish ACTH-independency. The appropriate management of BAI associated with cortisol excess remains controversial. Bilateral adrenalectomy results in lifetime steroid dependency and is better reserved only for patients with overt and severe hypercortisolism. Unilateral adrenalectomy might be considered in selected patients. Medical therapy is not an established approach yet but it may be considered when control of hypercortisolism is desired, but surgery is not an option.

Suprasellar extension independently predicts preoperative pituitary hormone deficiencies in patients with nonfunctioning pituitary macroadenomas: a single-center experience.

PURPOSE: Nonfunctioning pituitary adenomas (NFPAs) are among the commonest benign tumors of the pituitary. Hypopituitarism is frequently present at the time of diagnosis, and this has been attributed to stalk portal vessel compression and/or destruction of normal anterior pituitary cells. The aim of our study was to examine possible factors at diagnosis associated with the presence of hypopituitarism. METHODS: We retrospectively evaluated the records of patients with nonfunctioning pituitary macroadenomas from the database of our department. The inclusion criterion was the availability of imaging data regarding the extension of the lesion. RESULTS: A total of 148 patients (89 men, 60.1%) with nonfunctioning macroadenomas and available imaging data were identified. Mean age at diagnosis was 56.0 ± 14.5 years, and hypopituitarism was found in 66.2%. The maximum diameter of the adenoma, the patient's age at diagnosis, and compression of the optic chiasm were significant factors predicting the presence of hypopituitarism (OR 1.077, p = 0.006; OR 1.025, p = 0.045; and OR 2.893, p = 0.042, respectively). Suprasellar adenomas with extension to adjacent sinuses, although larger than those with only suprasellar extension, did not differ as to the degree of hypopituitarism. Moreover, in suprasellar adenomas, prolactin levels, albeit not independently, were also related to hypopituitarism (OR 1.035, p = 0.045). CONCLUSIONS: In patients with NFPAs, prognostic factors related to increased risk of hypopituitarism are age at diagnosis, size of the adenoma, and most importantly the presence of suprasellar extension. These data accentuate the necessity for surgical decompression in case of suprasellar extension, in order, apart from saving visual acuity, to possibly avoid or reverse hypopituitarism.

Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery.

CONTEXT: Patients with adrenal insufficiency require increased hydrocortisone cover during major stress to avoid a life-threatening adrenal crisis. However, current treatment recommendations are not evidence-based. OBJECTIVE: To identify the most appropriate mode of hydrocortisone delivery in patients with adrenal insufficiency who are exposed to major stress. DESIGN AND PARTICIPANTS: Cross-sectional study: 122 unstressed healthy subjects and 288 subjects exposed to different stressors (major trauma [N = 83], sepsis [N = 100], and combat stress [N = 105]). Longitudinal study: 22 patients with preserved adrenal function undergoing elective surgery. Pharmacokinetic study: 10 patients with primary adrenal insufficiency undergoing administration of 200 mg hydrocortisone over 24 hours in 4 different delivery modes (continuous intravenous infusion; 6-hourly oral, intramuscular or intravenous bolus administration). MAIN OUTCOME MEASURE: We measured total serum cortisol and cortisone, free serum cortisol, and urinary glucocorticoid metabolite excretion by mass spectrometry. Linear pharmacokinetic modeling was used to determine the most appropriate mode and dose of hydrocortisone administration in patients with adrenal insufficiency exposed to major stress. RESULTS: Serum cortisol was increased in all stress conditions, with the highest values observed in surgery and sepsis. Continuous intravenous hydrocortisone was the only administration mode persistently achieving median cortisol concentrations in the range observed during major stress. Linear pharmacokinetic modeling identified continuous intravenous infusion of 200 mg hydrocortisone over 24 hours, preceded by an initial bolus of 50-100 mg hydrocortisone, as best suited for maintaining cortisol concentrations in the required range. CONCLUSIONS: Continuous intravenous hydrocortisone infusion should be favored over intermittent bolus administration in the prevention and treatment of adrenal crisis during major stress.

Urine Steroid Metabolomics as a Novel Tool for Detection of Recurrent Adrenocortical Carcinoma.

CONTEXT: Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). OBJECTIVE, DESIGN, SETTING: This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. PATIENTS AND METHODS: 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography-mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. RESULTS: Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine "steroid fingerprint" at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). CONCLUSION: Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

Adrenal Imaging in Patients with Endocrine Hypertension.

Hypertension is one of the commonest chronic diseases contributing to cardiovascular disease. Idiopathic (primary) hypertension accounts for approximately 85% of the diagnosed cases, and 15% of hypertensive patients have other contributing conditions leading to elevated blood pressure (secondary hypertension). Endocrine hypertension is a common secondary cause of hypertension. The most common causes of endocrine hypertension are excess production of mineralocorticoids (ie, primary hyperaldosteronism), glucocorticoids (Cushing syndrome), and catecholamines (pheochromocytoma). After biochemical confirmation of hormonal excess, appropriate use of imaging modalities, both functional and anatomic, should occur for the diagnostic workup of these patients and for location of the source of hormonal excess.

Diagnosis and management of primary bilateral macronodular adrenal hyperplasia

Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a highly heterogeneous entity. The incidental identification of an increasing number of cases has shifted its clinical expression from the rarely encountered severe forms, regarding both cortisol excess and adrenal enlargement, to mild forms of asymptomatic or oligosymptomatic cases with less impressive imaging phenotypes. Activation of cAMP/PKA pathway, either due to alterations of the different downstream signaling pathways or through aberrantly expressed G-protein-coupled receptors, relates to both cortisol secretion and adrenal growth. Germline ARMC5 mutations are a frequent genetic defect. The diagnostic approach consists of both imaging and hormonal characterization. Imaging characterization should be done separately for each lesion. Endocrine evaluation in cases with clinically overt Cushing's syndrome (CS) is similar to that applied for all forms of CS. In incidentally detected PBMAH, hormonal evaluation includes testing for primary aldosteronism, pheochromocytoma and evaluation for autonomous cortisol secretion, using the 1 mg overnight dexamethasone suppression test. Midnight cortisol or 24-h urinary free cortisol may aid in establishing the degree of cortisol excess. In patients with hypercortisolism, ACTH levels should be measured in order to establish ACTH independency. At variance with other forms of CS, PBMAH may be characterized by a distinct pattern of inefficient steroidogenesis. The appropriate management of PBMAH remains controversial. Bilateral adrenalectomy results in lifetime steroid dependency and is better reserved only for patients with severe CS. Unilateral adrenalectomy might be considered in selected patients. In cases where the regulation of cortisol secretion is mediated by aberrant receptors there is some potential for medical therapy.

Medical therapy for non-functioning pituitary tumors-a critical approach.

Non-functioning pituitary adenomas (NFPAs) are the second most common variant of pituitary tumors. When symptomatic, primary therapy is surgery. Recurrence rates are high. Since many NFPAs express dopamine and somatostatin receptors, medical therapy has been used after surgery in order to prevent recurrence. So far, dopamine agonists have been more widely tested with some promise when introduced immediately after surgery but with less efficacy when introduced later upon tumor regrowth. Currently, the role of medical therapy to prevent tumor regrowth in NFPAs is limited by imprecisions as to final outcome and uncertainties concerning on patient selection, dosing, duration, and side effects.

Visceral adiposity index for the diagnosis of nonalcoholic fatty liver disease in premenopausal women with and without polycystic ovary syndrome.

OBJECTIVE: Visceral adiposity index (VAI), initially developed for the assessment of cardiometabolic risk, has been also proposed for the detection of nonalcoholic fatty liver disease (NAFLD); however, its diagnostic performance for NAFLD is still under investigation. We evaluated VAI as a marker of NAFLD and compared its diagnostic performance with that of three other NAFLD indices - fatty liver index (FLI), lipid accumulation product (LAP) and hepatic steatosis index (HSI) - in premenopausal women with and without polycystic ovary syndrome (PCOS) assessed for NAFLD by ultrasonography. DESIGN: Cross-sectional case-control study. METHODS: Anthropometric measurements, biochemical testing and abdominal ultrasonography after excluding causes of secondary liver disease were performed in 145 premenopausal women with PCOS (Rotterdam criteria) and 145 healthy control women within the same age range and matched for body mass index (BMI). The diagnostic performance of the four indices was assessed with receiver operating characteristic (ROC) analysis. RESULTS: NAFLD by ultrasonography was detected in 132 of the total sample of 290 women (45.5%). VAI, FLI, LAP and HSI values were significantly higher in women with NAFLD than those without. The areas under the curve (AUROCs) for VAI, FLI, LAP and HSI were 0.77 ±â€¯0.03, 0.87 ±â€¯0.02, 0.84 ±â€¯0.02 and 0.83 ±â€¯0.02, respectively, in the whole group, showing an adequate discriminatory ability for NAFLD of the four indices. AUROCs of the four indices calculated separately for PCOS and control women showed a similar performance of all indices in the two groups. CONCLUSIONS: These data show that VAI is useful for detecting NAFLD in premenopausal women with and without PCOS. However, VAI had a lower diagnostic performance in this cohort than FLI, LAP and HSI.

DIAGNOSIS OF ENDOCRINE DISEASE: The role of the desmopressin test in the diagnosis and follow-up of Cushing's syndrome.

Desmopressin is a vasopressin analogue selective for type 2 vasopressin receptors that mediate renal water retention. In contrast to the native hormone arginine vasopressin, a well-known ACTH secretagogue, desmopressin, exerts minimal or no activity on ACTH excretion. However, in a substantial proportion of patients with ACTH-dependent Cushing's syndrome (CS), desmopressin elicits an ACTH and cortisol response, which contrasts with the minimal responses obtained in healthy subjects. The mechanism underlying this paradoxical response involves upregulation of vasopressin type 3 and/or the aberrant expression of type 2 receptors by neoplastic ACTH-producing cells. This makes desmopressin administration a suitable test enabling the distinction between neoplastic from functional (formerly termed 'pseudo-Cushing syndrome') ACTH-dependent cortisol excess. Several studies have now established an adjunctive role of desmopressin in the initial diagnostic workup of CS. Despite some early data indicating that this test may also have a role in distinguishing between Cushing's disease (CD) and ectopic ACTH secretion, subsequent studies failed to confirm this observation. The ability of the paradoxical response to desmopressin to depict the presence of neoplastic ACTH-secreting cells was also exploited in the follow-up of patients with CD undergoing surgery. Loss of the desmopressin response, performed in the early postoperative period, was a good predictor for a favorable long-term outcome. Moreover, during follow-up, reappearance of desmopressin paradoxical response was an early indicator for recurrence. In conclusion, the desmopressin test is a valid tool in both the diagnosis and follow-up of patients with CD and should be more widely applied in the workup of these patients.

Cytomegalovirus reactivation in a general, nonimmunosuppressed intensive care unit population: incidence, risk factors, associations with organ dysfunction, and inflammatory biomarkers.

PURPOSE: Cytomegalovirus (CMV) reactivation, a significant cause of morbidity and mortality in immunosuppression, may affect "immunocompetent" seropositive critically ill patients. The aim of this prospective, observational study was to define the incidence, risk factors, and the association with morbidity and mortality of CMV reactivation in a general population of critically ill immunocompetent patients. We also studied the relationship between reactivation and patients' inflammatory response, as expressed by cytokine levels and stress up-regulation by salivary cortisol. METHODS: This study included mechanically ventilated CMV-seropositive patients. A quantitative real-time polymerase chain reaction (PCR) was performed for CMV plasma DNAemia determination, upon intensive care unit (ICU) admission and weekly thereafter until day 28. Cytomegalovirus reactivation was defined as CMV plasma DNAemia greater than or equal to 500 copies/mL. Upon ICU admission, interferon γ, interleukin (IL) 10, IL-17A, IL-2, IL-6, and tumor necrosis factor α were quantified in plasma, and morning saliva was obtained to measure cortisol. Disease severity was assessed by Acute Physiology and Chronic Health Evaluation II score, whereas the degree of organ dysfunction was quantified by Sequential Organ Failure Assessment score. Mortality, duration of mechanical ventilation, and ICU length of stay were recorded. RESULTS: During the study period, 80 (51 men) patients with a median age of 63 years fulfilled the inclusion criteria. Reactivation of CMV occurred in 11 patients (13.75%). Median day of reactivation was day 7 post ICU admission. Total number of red blood cell units transfused (odds ratio [OR], 1.50; confidence interval [CI], 1.06-2.13; P = .02) and C-reactive protein levels upon ICU admission (OR, 1.01; CI, 1.00-1.02; P = .02) were independently associated with CMV reactivation. High IL-10 was marginally related to reactivation (P = .06). Sequential Organ Failure Assessment scores were higher in the group with CMV reactivation compared with patients without reactivation during the entire 28-day observation period (P < .006). Salivary cortisol, mortality, length of ICU stay, and duration of mechanical ventilation were similar in the 2 groups. CONCLUSIONS: Cytomegalovirus reactivation occurred in 13.75% of critically ill, immunocompetent patients. The degree of inflammation and the total number of transfused red blood cells units constituted risk factors. Cytomegalovirus reactivation was associated with more severe of organ dysfunction, but not with a worse clinical outcome.

Serial changes in adiponectin and resistin in critically ill patients with sepsis: associations with sepsis phase, severity, and circulating cytokine levels.

PURPOSE: The aim of the present study was to describe the variation in adiponectin and resistin levels, 2 adipokines with opposing effects on metabolism, in mechanically ventilated patients with sepsis and their relationships to disease severity and cytokine levels. MATERIALS AND METHODS: An observational prospective study was conducted in a secondary/tertiary unit. Forty-one mechanically ventilated patients diagnosed as having sepsis were included in the study. The Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment scores were estimated. Adiponectin, resistin, and cytokines were measured upon sepsis diagnosis and every 3 to 4 days thereafter until day 30. Adiponectin and resistin were also measured in 40 controls. RESULTS: The patients had higher adiponectin (10.9 ± 6.1 µg/mL vs 6.0 ± 2.9 µg/mL, P < .001) and resistin (24.7 ng/mL vs 3.8 ng/mL, P < .001) levels compared with the controls. Adiponectin increased and resistin decreased significantly over time in the entire cohort. Resistin correlated with Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, interleukin (IL)-6, IL-8, and IL-10 and was significantly higher in severe sepsis/septic shock compared with sepsis. No correlations between adiponectin and clinical scores were noted. CONCLUSIONS: Adiponectin and resistin change reciprocally during the course of sepsis. Resistin relates to the severity of sepsis and the degree of inflammatory response. Adiponectin and resistin may play a critical role in the metabolic adaptations observed in sepsis.