Objective:
Adrenal crisis (AC) is a life-threatening complication of adrenal insufficiency (AI), which according to retrospective data represents a significant clinical complication. Here we aimed to ...prospectively assess incidence of AC and mortality associated with AC in patients with chronic AI.
Methods:
A total of 423 patients with AI (primary AI, n = 221; secondary AI, n = 202) were prospectively followed up for 2 years. Baseline assessment included a general questionnaire and detailed written instructions on glucocorticoid dose adaptation during stress. Patients received follow-up questionnaires every 6 months and were contacted by phone in case of reported adrenal crisis.
Results:
A total of 423 data sets were available for baseline analysis, and 364 patients (86%) completed the whole study. Sixy-four AC in 767.5 patient-years were documented (8.3 crises per 100 patient-years). Precipitating causes were mainly gastrointestinal infection, fever, and emotional stress (20%, respectively) but also other stressful events (eg, major pain, surgery, strenuous physical activity, heat, pregnancy) or unexplained sudden onset of AC (7%) were documented. Patients with a previous AC were at higher risk of crisis (odds ratio 2.85, 95% confidence interval 1.5–5.5, P < .01). However, no further risk factors could be identified. Ten patients died during follow-up; in four cases death was associated with AC (0.5 AC related deaths per 100 patient-years).
Conclusion:
Even in educated patients with chronic adrenal insufficiency, AC occurs in a substantial proportion of cases. Furthermore, we identified AC-associated mortality in approxoimately 6% of AC. Our findings further emphasize the need for improved management of AC in patients with chronic AI.
Background:
Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently.
Objective:
The aim of this study was to identify markers with prognostic value for ...patients in this clinical setting.
Design, Setting, and Participants:
From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I–III were identified. As an independent validation cohort, 250 patients from three European countries were included.
Outcome Measurements and Statistical Analysis:
Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS).
Results:
Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio HR for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10–19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone.
Conclusion:
This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.
Abstract
Context
Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the ...management of PA patients.
Objectives
To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS.
Design and settings
In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes.
Results
AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as <25%. A within-patient pairwise comparison of 402 AVS performed both under unstimulated and cosyntropin-stimulated conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but reduced lateralization rates (P < 0.001). Post-adrenalectomy outcomes were not improved by use of cosyntropin or more restrictive diagnostic criteria.
Conclusion
Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020)
Adrenal tumors autonomously producing cortisol cause Cushing's syndrome. We performed exome sequencing of 25 tumor-normal pairs and identified 2 subgroups. Eight tumors (including three carcinomas) ...had many somatic copy number variants (CNVs) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2 and protein-altering mutations in TP53 and RB1. Seventeen tumors (all adenomas) had no somatic CNVs or TP53 or RB1 mutations. Six of these had known gain-of-function mutations in CTNNB1 (β-catenin) or GNAS (Gαs). Six others had somatic mutations in PRKACA (protein kinase A (PKA) catalytic subunit) resulting in a p.Leu206Arg substitution. Further sequencing identified this mutation in 13 of 63 tumors (35% of adenomas with overt Cushing's syndrome). PRKACA, GNAS and CTNNB1 mutations were mutually exclusive. Leu206 directly interacts with the regulatory subunit of PKA, PRKAR1A. Leu206Arg PRKACA loses PRKAR1A binding, increasing the phosphorylation of downstream targets. PKA activity induces cortisol production and cell proliferation, providing a mechanism for tumor development. These findings define distinct mechanisms underlying adrenal cortisol-producing tumors.
Abstract
Context
Adrenal gland imaging is recommended by the current guidelines for the workup of primary aldosteronism (PA). However, its diagnostic performance has not been established in large, ...multiethnic cohorts of patients who undergo adrenal vein sampling (AVS) and adrenalectomy.
Objective
This work aims to assess the diagnostic accuracy of cross-sectional adrenal imaging.
Methods
This international multicenter study took place in tertiary referral centers. A total of 1625 PA patients seeking surgical cure were enrolled in an international study involving 19 centers in North America, Europe, Asia, and Australia. Of these, 1311 (81%) had imaging data available and 369 (23%), who received a final diagnosis of surgically cured unilateral PA, were examined. Patients underwent AVS and imaging by computed tomography and/or magnetic resonance imaging. The accuracy of detection of unilateral PA at imaging was estimated by the area under the receiver operator characteristics curve using cure (biochemical and/or full clinical success) as the reference at follow-up after unilateral adrenalectomy.
Results
In the cohort of 1311 patients with imaging data available, 34% and 7% of cases showed no detectable or bilateral nodules, respectively. Imaging did not detect the culprit adrenal in 28% of the surgically cured unilateral PA patients. Moreover, the clinical outcome did not differ significantly between the imaging-positive and imaging-negative patients.
Conclusion
Cross-sectional imaging did not identify a lateralized cause of disease in around 40% of PA patients and failed to identify the culprit adrenal in more than one-fourth of patients with unilateral PA.
The last years have seen substantial progress in primary aldosteronism (PA), which is the most common cause of secondary hypertension. Many programs have been established around the world to meet the ...needs in healthcare and the management of patients with PA according to published guidelines and clinical protocols. Systematic analysis of emerging data and meticulous scientific work have informed us on the molecular basis of the disease and helped to characterize hereditary forms of PA. Techniques have been developed to better diagnose PA and to establish genotype-phenotype relationships and their impact on hypertension. Studies have been undertaken to stratify patients for risk factors and to ensure quality of best medical treatment. This review focuses on some clinically relevant problems in characterizing autonomous aldosterone secretion and discusses testing and management strategies. Besides, this review puts the emphasis on some colorful studies not to pale soon beside an ever evolving painting background.
•LC–MS/MS based quantification of 15 steroids in peripheral and adrenal venous samples.•Sensitivity sufficient for reliable aldosterone measurements in peripheral plasma.•Utility for clinical work-up ...of primary aldosteronism due to included hybrid steroids.•AV/pV step-ups for most other steroids higher than for cortisol.•Cosyntropin stimulation during AVS changes relative adrenal secretion of steroid.
Steroid profiling for diagnosis of endocrine disorders featuring disordered production of steroid hormones is now possible from advances in liquid chromatography with tandem mass spectrometry (LC–MS/MS). Adrenal venous (AV) measurements of aldosterone and cortisol are a standard practice in the clinical work-up of primary aldosteronism, but do not yet take advantage of steroid profiling.
A novel LC–MS/MS based method was developed for simultaneous measurement of 15 adrenal steroids: aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, pregnenolone, cortisone, cortisol, 11-deoxycortisol, 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, 21-deoxycortisol, 18-oxocortisol and 18-hydroxycortisol. These were compared in peripheral venous (pV) and AV plasma from 70 patients undergoing AV sampling with and without cosyntropin stimulation. Aldosterone and cortisol levels measured by LC–MS/MS were compared with those measured by immunoassay.
Reproducibility of measurements with coefficients of variation ≤10% as well as analytical sensitivity sufficient to measure low pV levels particularly of aldosterone demonstrate the utility of the assay for profiling adrenal steroids in primary aldosteronism. Method comparisons indicated assay and concentration dependent differences of cortisol and aldosterone concentrations measured by immunoassay and LC–MS/MS. Median AV/pV ratios of 11-deoxycortisol (53.0), 17-hydroxyprogesterone (33.4), pregnenolone (62.4), androstenedione (40.6) and dehydroepiandrosterone (33.3) were 2.9- to, 5.4-fold larger than those for cortisol (11.6), with additionally generally larger increases than for cortisol with than without cosyntropin stimulation.
Our LC–MS/MS assay, in addition to improvements over existing immunoassay measurements of aldosterone and cortisol, offers profiling of 13 other adrenal steroids, providing a potentially useful method for the clinical work-up of patients with primary aldosteronism. In particular, the larger AV/pV ratios of several steroids compared to cortisol suggest more sensitive alternatives to the latter for assessing positioning of AV sampling catheters.
Context: No immunohistochemical marker has been established to reliably differentiate adrenocortical tumors from other adrenal masses. A panel of markers like melan-A and inhibin-α is currently used ...for this purpose but suffers from limited diagnostic accuracy. We hypothesized that expression of steroidogenic factor-1 (SF-1), a transcription factor involved in adrenal development, is of value for the differential diagnosis of adrenal masses and predicts prognosis in adrenocortical carcinoma (ACC).
Patients and Methods: SF-1 protein expression was assessed by immunohistochemistry on tissue samples from 167 ACC, 52 adrenocortical adenomas (ACA), six normal adrenal glands, six normal ovaries and 73 neoplastic nonsteroidogenic tissues. In an independent cohort of 33 ACC and 58 ACA, SF-1 mRNA expression was analyzed. SF-1 expression was correlated with clinical outcome in patients with ACC.
Results: SF-1 protein staining was detectable in 158 of 161 (98%) evaluable ACC samples including 49 (30%) with strong SF-1 staining and in all normal and benign steroidogenic tissues. In addition, SF-1 mRNA expression was present in all 91 analyzed adrenocortical tumors. In contrast, SF-1 expression was absent in all nonsteroidogenic tumors. Strong SF-1 protein expression significantly correlated with poor clinical outcome: tumor stage-adjusted hazard ratio for death 2.46 95% confidence interval (CI) = 1.30–4.64 and for recurrence 3.91 (95% CI = 1.71–8.94). Similar results were obtained in the independent cohort using RNA analysis tumor stage-adjusted hazard ratio for death 4.69 (95% CI = 1.44–15.30).
Conclusion: SF-1 is a highly valuable immunohistochemical marker to determine the adrenocortical origin of an adrenal mass with high sensitivity and specificity. In addition, SF-1 expression is of stage-independent prognostic value in patients with ACC.
SF-1 is currently the best immunohistological marker to determine the adrenocortical origin of an adrenal mass and has stage-independent prognostic value in adrenocortical carcinoma patients.
Context:
Pharmacological inhibition of mineralocorticoid receptor (MR) signaling in patients with primary aldosteronism (PA) reestablishes aldosterone synthesis by nondiseased zona glomerulosa cells ...through activation of the renin-angiotensin-aldosterone system. In this context, current guidelines recommend discontinuing MR blockade for diagnostic procedures, including adrenal vein sampling (AVS). Discontinuation of MR blockade in high-risk patients may be harmful because of uncontrolled hypertension and severe hypokalemia. We hypothesize that MR antagonist therapy can be continued during AVS as long as renin levels remain suppressed.
Objective:
The objective of this study was to assess the validity of AVS results in the context of MR antagonistic therapy.
Design:
We retrospectively analyzed all AVS studies in Munich (since 2008) and Düsseldorf (since 2011) and identified four of 237 (1.7%) patients with PA who underwent AVS while treated with an MR antagonist. Adrenalectomy was recommended based on the results of AVS in all four patients. After adrenalectomy, follow-up data were obtained to confirm improvement or remission of PA. Main outcome measures included blood pressure values, daily defined doses of antihypertensive medication, as well as levels of aldosterone, renin, and potassium, and the aldosterone/renin ratio.
Results:
In all patients, renin remained low or suppressed during AVS despite MR antagonist treatment. AVS clearly demonstrated unilateral aldosterone excess in each case. After adrenalectomy, all patients showed remission of PA as demonstrated by blood pressure values, potassium levels, and the aldosterone/renin ratio.
Conclusion:
In selected cases of PA, MR antagonist therapy might be continued during AVS, provided that renin values remain low.
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