Radiation exposure of adrenal vein sampling: a German Multicenter Study

Objective: Adrenal vein sampling (AVS) represents the current diagnostic standard for subtype differentiation in primary aldosteronism (PA). However, AVS has its drawbacks. It is invasive, expensive, requires an experienced interventional radiologist and comes with radiation exposure. However, exact radiation exposure of patients undergoing AVS has never been examined. Design and Methods: We retrospectively analyzed radiation exposure of 656 AVS performed between 1999 and 2017 at four university hospitals. The primary outcomes were dose area product (DAP) and fluoroscopy time (FT). Consecutively the effective dose (ED) was approximately calculated. Results: Median DAP was found to be 32.5 Gy*cm2 (0.3­3181) and FT 18 min (0.3­184). The calculated ED was 6.4 mSv (0.1­636). Remarkably, values between participating centers highly varied: Median DAP ranged from 16 to 147 Gy*cm2, FT from 16 to 27 min, and ED from 3.2 to 29 mSv. As main reason for this variation, differences regarding AVS protocols between centers could be identified, such as number of sampling locations, frames per second and the use of digital subtraction angiographies. Conclusions: This first systematic assessment of radiation exposure in AVS not only shows fairly high values for patients, but also states notable differences among the centers. Thus, we not only recommend taking into account the risk of radiation exposure, when referring patients to undergo AVS, but also to establish improved standard operating procedures to prevent unnecessary radiation exposure.

[Adrenal crisis]. / Nebennierenkrise.

Patients with chronic adrenal insufficiency suffer from reduced quality of life and increased mortality. An association between mortality and adrenal crisis is assumed. The frequency of adrenal crisis is about 8/100 patient years. The main causes are infectious disease. Pathophysiology is poorly understood to date. An association with an exaggerated inflammatory response due to a lack of glucocorticoid modulation as well as mineralocorticoid deficiency and diminished adrenomedullary function are discussed. The therapy of adrenal crisis includes prompt parenteral administration of hydrocortisone combined with isotonic saline. To prevent adrenal crisis, patients are equipped with an emergency card and set and educated in glucocorticoid dose adjustment.

[Addison's disease : Primary adrenal insufficiency]. / Morbus Addison : Primäre Nebenniereninsuffizienz.

Adrenal insufficiency, a rare disorder which is characterized by the inadequate production or absence of adrenal hormones, may be classified as primary adrenal insufficiency in case of direct affection of the adrenal glands or secondary adrenal insufficiency, which is mostly due to pituitary or hypothalamic disease. Primary adrenal insufficiency affects 11 of 100,000 individuals. Clinical symptoms are mainly nonspecific and include fatigue, weight loss, and hypotension. The diagnostic test of choice is dynamic testing with synthetic ACTH. Patients suffering from chronic adrenal insufficiency require lifelong hormone supplementation. Education in dose adaption during physical and mental stress or emergency situations is essential to prevent life-threatening adrenal crises. Patients with adrenal insufficiency should carry an emergency card and emergency kit with them.

Prevalence of Malignancies in Patients With Primary Aldosteronism.

CONTEXT: Primary aldosteronism (PA) is the most common cause of secondary hypertension. Aldosterone excess can cause DNA damage in vitro and in vivo. Single case reports have indicated a coincidence of PA with renal cell carcinoma and other tumors. However, the prevalence of benign and malignant neoplasms in patients with PA has not yet been studied. PATIENTS AND DESIGN: In the multicenter MEPHISTO study, the prevalence of benign and malignant tumors was investigated in 335 patients with confirmed PA. Matched hypertensive subjects from the population-based Study of Health in Pomerania cohort served as controls. RESULTS: Of the 335 PA patients, 119 (35.5%) had been diagnosed with a tumor at any time, and 30 had two or more neoplasms. Lifetime malignancy occurrence was reported in 9.6% of PA patients compared to 6.0% of hypertensive controls (P = .08). PA patients with a history of malignancy had higher baseline aldosterone levels at diagnosis of PA (P = .009), and a strong association between aldosterone levels and the prevalence of malignancies was observed (P = .03). In total, 157 neoplasms were identified in the PA patients; they were benign in 61% and malignant in 25% of the cases (14% of unknown dignity). Renal cell carcinoma was diagnosed in five patients (13% of all malignancies) and was not reported in controls CONCLUSION: Compared to hypertensive controls, the prevalence of malignancies was positively correlated with aldosterone levels, tended to be higher in PA patients, but did not differ significantly.

Prognostic factors in stage III-IV adrenocortical carcinomas (ACC): an European Network for the Study of Adrenal Tumor (ENSAT) study.

BACKGROUND: The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. PATIENTS AND METHODS: Patients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 'before surgery'; model 2 'post-surgery'. RESULTS: Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P < 0.0001), as well as additional parameters: age ≥ 50 years (P < 0.0001), tumor- or hormone-related symptoms (P = 0.01 and 0.03, respectively) in model 1 but also the R status (P = 0.001) and Grade (Weiss >6 and/or Ki67 ≥ 20%, P = 0.06) in model 2. CONCLUSION: The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.

Assay characteristics influence the aldosterone to renin ratio as a screening tool for primary aldosteronism: results of the German Conn's registry.

Primary aldosteronism (PA) is the most frequent cause of secondary arterial hypertension. The aldosterone to renin ratio (ARR) is the gold standard for screening, but variability between biochemical methods used remains of concern. The aim of the study was to analyze center-specific features of biochemical diagnostic strategies prior to the 2008 consensus within the German Conn's Registry. The study was designed as a retrospective study in 5 tertiary care hospitals. Patients analyzed for PA between 1990 and 2006 were studied. Characteristics of the assays used to determine ARR during establishing the diagnosis of PA were analyzed in the retrospective part of the German Conn's Registry. Eighty-six out of 484 documented ARR values had to be excluded from further evaluations because the laboratory or the assays were unknown. In the remaining 398 patients ARR was determined using 10 different assay combinations in the centers (aldosterone plus plasma renin activity or concentration). Considerable differences were seen between the mean concentrations for aldosterone (p<0.0001), renin concentration (p<0.001), and renin activity (p=0.009) for the different assays. The differences between the absolute concentrations measured by the different assays also had significant impact upon the resulting mean ratios. If published cutoff values are applied, the use of different commercial assays to determine the ARR in clinical routine results in major differences in positive screening rates. This heterogeneity affects sensitivity and specificity of screening for PA. Our data emphasize the importance of standardized screening procedures, which must include standardization of biochemical methods.

[A 47-year-old patient with paroxysmal arterial hypertension and gastric tumors]. / 47-jährige Patientin mit paroxysmaler arterieller Hypertonie und gastralen Raumforderungen.

Arterial hypertension caused by a paraganglioma is rare and approximately one third of all cases of paraganglioma occur as part of a hereditary syndrome. Among these the Carney-Stratakis syndrome is characterized by the occurrence of paraganglioma/pheochromocytoma and gastrointestinal stromal tumors caused by germline mutations of the succinate dehydrogenase subunit genes (B-D). We report the case of a 47-year-old female patient suffering from Carney-Stratakis syndrome with an endocrine active thoracic paraganglioma which was successfully resected with the assistance of a heart-lung machine and the gastric stromal tumors were removed in a second surgical intervention.

Metomidate-based imaging of adrenal masses.

Due to broader use of conventional imaging techniques, adrenal tumors are detected with increasing frequency comprising a wide variety of different tumor entities. Despite improved conventional imaging techniques, a significant number of adrenal lesions remain that cannot be easily determined. A particular diagnostic challenge are lesions in patients with known extra-adrenal malignancy because these patients frequently harbor adrenal metastases. Furthermore, adrenal masses with low fat content and no detectable hormone excess are difficult to diagnose properly. Fine needle biopsy is invasive, often unsuccessful, and puts patients at risk, e. g., in cases of pheochromocytoma or adrenal cancer. Noninvasive characterization using radiotracers has therefore been established in recent years. (18)F-FDG PET helps to differentiate benign from malignant lesions. However, it does not distinguish between adrenocortical or nonadrenocortical lesions (e.g., metastases or adrenocortical carcinoma). More recently, enzyme inhibitors have been developed as tracers for adrenal imaging. Metomidate is most widely used. It binds with high specificity and affinity to CYP11B enzymes of the adrenal cortex. As these enzymes are exclusively expressed in adrenocortical cells, uptake of labeled metomidate tracers has been shown to be highly specific for adrenocortical neoplasia. (11)C-metomidate PET and (123)I-iodometomidate SPECT imaging has been introduced into clinical use. Both tracers not only distinguish between adrenocortical and nonadrenocortical lesions but are also able to visualize metastases of adrenocortical carcinoma. The very specific uptake has recently led to first application of (131)I-iodometomidate for radiotherapy in ACC. In conclusion, metomidate-based imaging is an important complementary tool to diagnose adrenal lesions that cannot be determined by other methods.

Etomidate unmasks intraadrenal regulation of steroidogenesis and proliferation in adrenal cortical cell lines.

To characterize intraadrenal adaptations for inhibition of cortisol synthesis, we analyzed the effects of etomidate (ETO) on steroid hormone secretion and expression of key regulators of steroidogenesis and proliferation in human NCI-h295 adrenocortical cancer cells. Etomidate potently blocked 11beta-hydroxylase (CYP11B1), aldosterone synthase (CYP11B2), and side chain cleavage enzyme (CYP11A1). This inhibition of steroidogenesis was associated with increased expression of steroidogenic acute regulatory protein (StAR), and CYP11A1 and 17alpha-hydroxylase/17, 20-lyase (CYP17A1) protein levels, but not of the respective mRNA levels. Promoter activity of CYP11A1 and melanocortin 2 receptor (MC2R) was not increased by etomidate in treated cells compared to controls. The increase in protein levels was partially reversed by cycloheximide suggesting post-transcriptional mechanisms but also protein stabilization as underlying cause. Furthermore, ETO exhibited antiproliferative activity paralleled by a decrease in phosphorylation of MEK and ERK1, 2. In summary, ETO exhibits pleiotropic effects on adrenal function in vitro. Inhibition of steroidogenesis is followed by increased levels of steroidogenic key proteins and reduced proliferation. These changes reflect adaptations to maintain steroidogenesis at the cost of adrenal proliferation.

Is primary aldosteronism associated with diabetes mellitus? Results of the German Conn's Registry.

Aldosterone excess in the context of primary aldosteronism (PA) has been associated with impaired glucose tolerance and diabetes mellitus. We retrospectively assessed the prevalence of diabetes mellitus in patients from the German Conn's Register and compared the data with those from hypertensive subjects of a population-based survey. In a case-control study, we have compared 638 patients with PA from the German Conn's registry who were treated in 6 German centers with 897 hypertensive control subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg (KORA). The samples were matched for age, sex, and blood pressure in a 1:1 ratio. Risk factors associated with the presence of diabetes mellitus were calculated in 638 patients with PA and 897 hypertensive controls. In the case control study, the diabetes prevalence was calculated in 338 cases and controls. In patients with primary aldosteronism, age, BMI, and a higher number of antihypertensive drugs (lowest tertile vs. highest tertile) were variables associated with diabetes mellitus. In contrast, serum potassium and plasma aldosterone concentrations were not associated with higher diabetes prevalence, whereas diastolic blood pressure was inversely associated with diabetes mellitus. Diabetes mellitus was more prevalent in patients with PA than in 338 matched controls (23 vs. 10% in controls). Our data for the German population show that diabetes mellitus is more prevalent in patients with primary aldosteronism than in hypertensive controls.

Evaluation of a standardized protocol for processing adrenal tumor samples: preparation for a European adrenal tumor bank.

Storage and tissue handling of surgical tumor specimen have been recognized as critical steps that can potentially affect reproducibility and comparability of molecular endpoints between laboratories. In the preparation of adrenal tumor tissue banking, three different protocols that simulate warm ischemia upon tumor removal (protocol I), thawing and refreezing cycles (protocol II), as well as storage of vital tumor samples (protocol III) were applied. For the first two protocols, samples were subdivided and either snap frozen or treated with a RNA preserving agent (RPA) while in protocol III different storage media were compared. Following these procedures, recovery and integrity of DNA, RNA, and protein by means of pulsed field electrophoresis, long-range PCR, real-time PCR, immunoblot, and immunohistochemistry (protocol I and II) as well as cell viability and steroidogenic capacity (protocol III) were investigated. While DNA integrity was not influenced by different treatment modalities, expression levels of adrenal marker genes were more affected in samples after snap freezing in comparison to RPA pretreatment. Moreover, storage at room temperature before and after freezing could be demonstrated to decrease the relative amount of protein phosphorylation (ERK) and enzymatic activity (succinate cytochrome c reductase) while overall protein levels were not significantly affected. Similarly, morphological or immunohistochemical evaluation was comparable between groups. For primary cell cultures generated after storage of tumor samples similar rates of viability were observable while steroid output varied between the groups. Overall, on the basis of the presented endpoints standardized operational procedures can be defined for a proposed European adrenal tumor biobank.

Merits and pitfalls of mifepristone in Cushing's syndrome.

OBJECTIVE: Mifepristone is the only available glucocorticoid receptor antagonist. Only few adult patients with hypercortisolism were treated to date by this drug. Our objective was to determine effectiveness and tolerability of mifepristone in Cushing's syndrome (CS). DESIGN: Retrospective study of patients treated in seven European centers. METHODS: Twenty patients with malignant (n=15, 12 with adrenocortical carcinoma, three with ectopic ACTH secretion) or benign (n=5, four with Cushing's disease, one with bilateral adrenal hyperplasia) CS were treated with mifepristone. Mifepristone was initiated with a median starting dose of 400 mg/day (200-1000). Median treatment duration was 2 months (0.25-21) for malignant CS, and 6 months (0.5-24) for benign CS. Clinical (signs of hypercortisolism, blood pressure, signs of adrenal insufficiency), and biochemical parameters (serum potassium and glucose) were evaluated. RESULTS: Treatment was stopped in one patient after 1 week due to severe uncontrolled hypokalemia. Improvement of clinical signs was observed in 11/15 patients with malignant CS (73%), and 4/5 patients with benign CS (80%). Psychiatric symptoms improved in 4/5 patients within the first week. Blood glucose levels improved in 4/7 patients. Signs of adrenal insufficiency were observed in 3/20 patients. Moderate to severe hypokalemia was observed in 11/20 patients and increased blood pressure levels in 3/20 patients. CONCLUSION: Mifepristone is a rapidly effective treatment of hypercortisolism, but requires close monitoring of potentially severe hypokalemia, hypertension, and clinical signs of adrenal insufficiency. Mifepristone provides a valuable treatment option in patients with severe CS when surgery is unsuccessful or impossible.

Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn's Registry.

CONTEXT: Primary aldosteronism (PA) is associated with vascular end-organ damage. OBJECTIVE: Our objective was to evaluate differences regarding comorbidities between the hypokalemic and normokalemic form of PA. DESIGN AND SETTING: This was a retrospective cross-sectional study collected from six German centers (German Conn's registry) between 1990 and 2007. PATIENTS: Of 640 registered patients with PA, 553 patients were analyzed. MAIN OUTCOME MEASURES: Comorbidities depending on hypokalemia or normokalemia were examined. RESULTS: Of the 553 patients (61 +/- 13 yr, range 13-96), 56.1% had hypokalemic PA. The systolic (164 +/- 29 vs. 155 +/- 27 mm Hg; P < 0.01) and diastolic (96 +/- 18 vs. 93 +/- 15 mm Hg; P < 0.05) blood pressures were significantly higher in hypokalemic patients than in those with the normokalemic variant. The prevalence of cardiovascular events (angina pectoris, myocardial infarction, chronic cardiac insufficiency, coronary angioplasty) was 16.3%. Atrial fibrillation occurred in 7.1% and other atrial or ventricular arrhythmia in 5.2% of the patients. Angina pectoris and chronic cardiac insufficiency were significantly more prevalent in hypokalemic PA (9.0 vs. 2.1%, P < 0.001; 5.5 vs. 2.1%, P < 0.01). Overall, cerebrovascular comorbidities were not different between hypokalemic and normokalemic patients, however, stroke tended to be more prevalent in normokalemic patients. CONCLUSIONS: Our data indicate a high prevalence of comorbidities in patients with PA. The hypokalemic variant is defined by a higher morbidity than the normokalemic variant regarding some cardiovascular but not cerebrovascular events. Thus, PA should be sought not only in hypokalemic but also in normokalemic hypertensives because high-excess morbidity occurs in both subgroups.

[Replacement therapy with adrenal steroids]. / Substitution mit Nebennierensteroiden.

Replacement with adrenal steroids comprises treatment with glucocorticoids, mineralocorticoids and adrenal androgen precursors, mainly in patients with adrenal insufficiency. Attention has also been directed to replacement treatment with glucocorticoids in critically ill patients or with dehydroepiandrosterone (DHEA) in elderly people with an age related decline of DHEA/DHEAS levels. Despite the use of current replacement concepts well-being is often not fully restored in patients with adrenal insufficiency. Innovations comprise the development of new delayed release glucocorticoid preparations that allow to better mimic the circadian cortisol secretion and may have the potential to improve the treatment of patients with adrenal insufficiency. Recent results from the CORTICUS study have not confirmed previous beneficial results and have led to restrictions in the use of hydrocortisone substitution therapy in patients with septic shock. Treatment with the androgen precursor DHEA in patients with adrenal insufficiency may improve quality of life. However, in patients with an age related decline of DHEA levels, the available evidence does not support the use of DHEA replacement as an anti aging treatment.

[Adrenocortical carcinoma. Diagnostic work-up and treatment]. / Das Nebennierenkarzinom. Diagnostik und Therapie.

Adrenocortical carcinoma (ACC) is a rare disease with poor prognosis. Preoperatively, a thorough hormonal work-up is mandatory, as the hormonal status may influence the perioperative management and may also provide marker hormones for monitoring of tumour recurrence. CT and MRI are equally sensitive and specific imaging tools for adrenal tumours. For discerning malignancy, assessment of the fat content of the tumour and contrast media wash-out after 10 min are of great value. Complete surgical resection of the tumour offers the only chance for cure. Open adrenalectomy via a flank or thoracoabdominal approach is the standard surgical technique. Intraoperative tumour spillage should be carefully avoided. Even after R0 resection, recurrence of the disease is frequent and regular follow-up for a minimum of 5 years is required. In advanced ACC, the treatment of choice is mitotane with or without cytotoxic chemotherapy (preferably after inclusion into the FIRM-ACT trial).

DHEA: why, when, and how much--DHEA replacement in adrenal insufficiency.

In recent years it has been demonstrated that current replacement therapy with glucocorticoids and mineralocorticoids fails to fully restore health-related quality of life in patients with adrenal insufficiency (AI). Accordingly, replacement of zona reticularis function by DHEA is of considerable interest. Available studies have demonstrated beneficial effects of DHEA on health perception, vitality, fatigue, and (in women) sexuality. DHEA restores low circulating androgens in women into the normal range and increases IGF-1 levels. Side effects are mostly mild and related to androgenic activity of DHEA in women and include increased sebum production, facial acne, and changes in hair status. Replacement consists of a single oral dose of 25-50 mg DHEA in the morning. However, not all investigators have found effects of DHEA on well-being, most likely because of small sample size and short duration of treatment. Thus, to fully explore the role of DHEA in the treatment of AI large trials for 12-24 months are still urgently needed. Until the results of such trials are available DHEA cannot be considered part of standard replacement in AI, but compassionate use of DHEA in individual patients with AI and impaired well-being may be justified.

Adrenocortical carcinoma -- improving patient care by establishing new structures.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and highly malignant tumour with a poor prognosis. Patients present with signs of steroid hormone excess (e.g., Cushing's syndrome) or symptoms due to an abdominal mass. DIAGNOSIS: In case of an adrenal mass, hormonal workup before surgery is required for differential diagnosis, perioperative management, and for follow-up. The imaging of choice is CT or MRI with MRI being of additional use when invasion of big vessels is suspected. Apart from that, the use of 18-FDG-PET is becoming increasingly established. TREATMENT: Surgical resection is the therapeutic option of choice in stages 1 - 3. In stage 4, the adrenolytic compound mitotane is part of the first-line treatment, but often needs to be combined with cytotoxic chemotherapy. Most patients will eventually have a recurrence, so adjuvant treatment (mitotane/tumour bed radiation) has to be considered in high risk patients, even if randomized controlled trials on adjuvant treatment are still lacking. STRUCTURAL PROGRESS: Several national and European structures have recently been established in order to increase our knowledge of ACC, improve therapeutic options and diagnostic procedures, and promote research. GANIMED, as a Germany-wide network of experts on adrenal diseases, has been founded allowing for improved gathering of data and joint studies. ENSAT (European Network for the Study of Adrenal Tumours) has been brought to life, aiming at European standards for therapy, diagnosis and tumour banking. Since 2003, patients can be enrolled in the German ACC Registry. France and Italy have also developed a central registry to collect nationwide data from patients with ACC. For the first time, patients with metastatic/unresectable ACC can participate in a prospective controlled randomized trial comparing two different cytotoxic chemotherapy regimes (FIRM-ACT).

[Adrenal crisis. Diagnostic and therapeutic management of acute adrenal cortex insufficiency]. / Die Nebennierenkrise. Diagnostisches und therapeutisches Management der akuten Nebennierenrindeninsuffizienz.

Acute adrenal insufficiency is a rare but life-threatening disorder that develops as a result of inadequate adrenal steroid production. Early diagnosis is key for effective and life-saving treatment of the affected patients. The main clinical features are non-specific, thus often leading to misdiagnosis and invasive diagnostic work up, in particular in patients with previously unknown disease. Adrenal crisis in patients with known chronic adrenal insufficiency is nowadays rare, but can only be prevented by structured patient education on stress-related glucocorticoid dose adjustment. Outcome of adrenal crisis is crucially determined by the physician's clinical competence and immediate initiation of specific treatment.