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Free access

Stephan Petersenn, Albert Beckers, Diego Ferone, Aart van der Lely, Jens Bollerslev, Marco Boscaro, Thierry Brue, Paolo Bruzzi, Felipe F Casanueva, Philippe Chanson, Annamaria Colao, Martin Reincke, Günter Stalla, and Stelios Tsagarakis

Objective

A number of factors can influence the reported outcomes of transsphenoidal surgery (TSS) for Cushing's disease – including different remission and recurrence criteria, for which there is no consensus. Therefore, a comparative analysis of the best treatment options and patient management strategies is difficult. In this review, we investigated the clinical outcomes of initial TSS in patients with Cushing's disease based on definitions of and assessments for remission and recurrence.

Methods

We systematically searched PubMed and identified 44 studies with clear definitions of remission and recurrence. When data were available, additional analyses by time of remission, tumor size, duration of follow-up, surgical experience, year of study publication and adverse events related to surgery were performed.

Results

Data from a total of 6400 patients who received microscopic TSS were extracted and analyzed. A variety of definitions of remission and recurrence of Cushing's disease after initial microscopic TSS was used, giving broad ranges of remission (42.0–96.6%; median, 77.9%) and recurrence (0–47.4%; median, 11.5%). Better remission and recurrence outcomes were achieved for microadenomas vs macroadenomas; however, no correlations were found with other parameters, other than improved safety with longer surgical experience.

Conclusions

The variety of methodologies used in clinical evaluation of TSS for Cushing's disease strongly support the call for standardization and optimization of studies to inform clinical practice and maximize patient outcomes. Clinically significant rates of failure of initial TSS highlight the need for effective second-line treatments.

Restricted access

Anton Köhler, Anna-Lina Sarkis, Daniel Alexander Heinrich, Lisa Müller, Laura Handgriff, Sinan Deniz, Holger Schneider, Heike Künzel, Roland Ladurner, Martin Reincke, and Christian Adolf

Context

Primary aldosteronism (PA) causes left ventricular hypertrophy (LVH) via hemodynamic factors and directly by aldosterone effects. Specific treatment by mineralocorticoid receptor antagonists (MRA) or adrenalectomy (ADX) has been reported to improve LVH. However, the cardiovascular benefit could depend on plasma renin concentration (PRC) in patients on MRA.

Patients and objective

We analyzed data from 184 patients from the Munich center of the German Conn’s Registry, who underwent echocardiography at the time of diagnosis and 1 year after treatment. To assess the effect of PRC on cardiac recovery, we stratified patients on MRA according to suppression (n = 46) or non-suppression of PRC (n = 59) at follow-up and compared them to PA patients after ADX (n = 79).

Results

At baseline, patients treated by ADX or MRA had comparable left ventricular mass index (LVMI, 61.7 vs 58.9 g/m2.7, P  = 0.591). Likewise, patients on MRA had similar LVMI at baseline, when stratified into treatment groups with suppressed and unsuppressed PRC during follow-up (60.0 vs 58.1 g/m2.7, P  = 0.576). In all three groups, we observed a significant reduction in LVMI following treatment (P  < 0.001). However, patients with suppressed PRC had no decrease in pro-BNP levels, and the reduction of LVMI was less intense than in patients with unsuppressed PRC (4.1 vs 8.2 g/m2.7, P  = 0.033) or after ADX (9.3 g/m2.7, P  = 0.019). Similarly, in multivariate analysis, higher PRC was correlated with the regression of LVH.

Conclusion

PA patients with suppressed PRC on MRA show impaired regression of LVH. Therefore, dosing of MRA according to PRC could improve their cardiovascular benefit.

Free access

Christina M Berr, Mareike R Stieg, Timo Deutschbein, Marcus Quinkler, Ralf Schmidmaier, Andrea Osswald, Nicole Reisch, Katrin Ritzel, Christina Dimopoulou, Julia Fazel, Stefanie Hahner, Günter K Stalla, Felix Beuschlein, and Martin Reincke

Background

Cushing’s syndrome (CS) is characterized by an excessive secretion of glucocorticoids that results in a characteristic clinical phenotype. One feature of clinical hypercortisolism is breakdown of protein metabolism translating into clinical consequences including glucocorticoid-induced myopathy. While surgery is effective in control of cortisol excess, the effect of biochemical remission on muscular function is yet unclear.

Methods

In a cross-sectional study we analyzed 47 patients with CS during the florid phase (ActiveCS). 149 additional patients were studied 2–53 years (mean: 13 years) after surgery in biochemical long-term remission (RemissionCS). Also, 93 rule-out CS patients were used as controls (CON). All subjects were assessed for grip strength using a hand grip dynamometer and underwent the chair rising test (CRT).

Results

Hand grip strength (85% vs 97% of norm, P = 0.002) and the CRT performance (9.5 s vs 7.1 s, P = 0.001) were significantly lower in ActiveCS compared to the CON group. Six months after treatment grip strength further decreased in CS (P = 0.002) and CRT performance remained impaired. The RemissionCS group (mean follow-up 13 years) had reduced hand grip strength (92% compared to normal reference values for dominant hand, P < 0.001). The chair rising test performance was at 9.0 s and not significantly different from the ActiveCS group (P = 0.45).

Conclusion

CS affects muscle strength in the acute phase, but functional impairment remains detectable also during long-term follow-up despite biochemical remission.

Free access

Daniel A Heinrich, Christian Adolf, Marcus Quinkler, Finn Holler, Benjamin Lechner, Nina Nirschl, Lisa Sturm, Veronika Görge, Felix Beuschlein, and Martin Reincke

Objective

Saline infusion test (SIT) and captopril challenge test (CCT) are standard confirmatory procedures routinely used in the diagnostic work-up of primary aldosteronism (PA). However, side effects and complications during testing have not been systematically studied.

Design

We performed a cohort study with patients undergoing SIT and/or CCT in two centers from 2016 until 2018.

Methods

We studied 272 study participants with suspected PA enrolled at two outpatient centers in Germany. We assessed the frequency and severity of side effects during adjustment of blood pressure medication and during SIT and CCT.

Results

During the adjustment phase prior confirmatory testing, side effects including palpitations, headaches, edema and hypertensive episodes occurred in 18.4% of study participants. Side effects were associated with higher defined daily doses (DDD) (r = 0.25, P < 0.005), number of antihypertensive drugs (r = 0.285, P < 0.005) and higher blood pressure (r = 0.145, P = 0.019). During SIT, 17.5% of study participants had side effects, associated with higher blood pressure (systolic: r = 0.541, P < 0.0005; diastolic: r = 0.426, P < 0.0005) and DDDs (r = 0.727, P < 0.0005). During CCT, only 1.5% of study participants developed side effects.

Conclusions

In contrast to the high rate of side effects during SIT, CCT appears to be the safer test with a very low event rate. This makes CCT especially suitable for severely hypertensive patients.

Free access

Verena Fourkiotis, Oliver Vonend, Sven Diederich, Evelyn Fischer, Katharina Lang, Stephan Endres, Felix Beuschlein, Holger S Willenberg, Lars C Rump, Bruno Allolio, Martin Reincke, Marcus Quinkler, and for the Mephisto Study Group

Objective

Primary aldosteronism (PA) has deleterious effects on kidney function independent of blood pressure levels. Up to now, data on effectiveness of different PA therapies regarding renal function are scarce.

Design and methods

This prospective multi-center study included 29 patients with newly diagnosed PA evaluated before and 1 year after treatment initiation, and a second cohort including 119 patients who were evaluated 5.3 and 6.8 years after treatment initiation. Glomerular filtration rate (GFR), spot urine albumin excretion/urinary creatinine (UAE/Ucrea) ratio, biochemical parameters, and 24-h blood pressure were measured. In a larger cross-sectional cohort, renal function was evaluated depending on the type of treatment (adrenalectomy (ADX; n=86); spironolactone (n=65); and eplerenone (n=18)).

Results

GFR and UAE/Ucrea ratio significantly decreased in newly diagnosed PA patients after treatment initiation. In the second cohort, GFR and UAE/Ucrea ratio did not change during study period, and blood pressure was well controlled. In the larger cross-sectional cohort, no differences were seen in GFR and UAE/Ucrea ratio between PA patients on different treatment regimens. However, eplerenone treatment showed lower potassium levels and higher number of required antihypertensive medications.

Conclusions

Renal dysfunction with elevated albuminuria was seen in PA patients and was reversible after treatment initiation. Medical therapies with spironolactone or eplerenone seem to be as effective as ADX regarding renal function and blood pressure; however, sufficient daily doses need to be given.

Free access

Gregor Hanslik, Henri Wallaschofski, Anna Dietz, Anna Riester, Martin Reincke, Bruno Allolio, Katharina Lang, Ivo Quack, Lars C Rump, Holger S Willenberg, Felix Beuschlein, Marcus Quinkler, Anke Hannemann, and for the participants of the German Conn's Registry

Design

Abnormalities in glucose homeostasis have been described in patients with primary aldosteronism (PA) but most studies show inconsistent results. Therefore, we aimed to compare the prevalence of type 2 diabetes mellitus and metabolic syndrome (MetS) in newly diagnosed PA patients to a matched control cohort of the background population.

Methods

In total, 305 PA patients of the prospective German Conn's Registry were compared to the population-based Study of Health In Pomerania (SHIP1; n=2454). A 1:1 match regarding sex, age, and BMI resulted in 269 matched pairs regarding type 2 diabetes and 183 matched pairs regarding MetS. Of the total, 153 PA patients underwent oral glucose tolerance testing (OGTT) at diagnosis and 38 PA patients were reevaluated at follow-up.

Results

Type 2 diabetes and MetS were significantly more frequent in PA patients than in the control population (17.2% vs 10.4%, P=0.03; 56.8% vs 44.8%, P=0.02 respectively). Also, HbA1c levels were higher in PA patients than in controls (P<0.01). Of the total, 35.3% of non-diabetic PA patients showed an abnormal OGTT (¼ newly diagnosed type 2 diabetes and ¾ impaired glucose tolerance). PA patients with an abnormal OGTT at baseline presented with significantly improved 2 h OGTT glucose (P=0.01) at follow-up. We detected a negative correlation between 2 h OGTT glucose levels and serum potassium (P<0.01).

Conclusions

Type 2 diabetes and MetS are more prevalent in patients with PA than in controls matched for sex, age, BMI, and blood pressure. This may explain in part the increased cardiovascular disease morbidity and mortality in PA patients.

Free access

Vincent L Wester, Martin Reincke, Jan W Koper, Erica L T van den Akker, Laura Manenschijn, Christina M Berr, Julia Fazel, Yolanda B de Rijke, Richard A Feelders, and Elisabeth F C van Rossum

Objective

Current first-line screening tests for Cushing’s syndrome (CS) only measure time-point or short-term cortisol. Hair cortisol content (HCC) offers a non-invasive way to measure long-term cortisol exposure over several months of time. We aimed to evaluate HCC as a screening tool for CS.

Design

Case-control study in two academic referral centers for CS.

Methods

Between 2009 and 2016, we collected scalp hair from patients suspected of CS and healthy controls. HCC was measured using ELISA. HCC was available in 43 confirmed CS patients, 35 patients in whom the diagnosis CS was rejected during diagnostic work-up and follow-up (patient controls), and 174 healthy controls. Additionally, we created HCC timelines in two patients with ectopic CS.

Results

CS patients had higher HCC than patient controls and healthy controls (geometric mean 106.9 vs 12.7 and 8.4 pg/mg respectively, P < 0.001). At a cut-off of 31.1 pg/mg, HCC could differentiate between CS patients and healthy controls with a sensitivity of 93% and a specificity of 90%. With patient controls as a reference, specificity remained the same (91%). Within CS patients, HCC correlated significantly with urinary free cortisol (r = 0.691, P < 0.001). In two ectopic CS patients, HCC timelines indicated that cortisol was increased 3 and 6 months before CS became clinically apparent.

Conclusions

Analysis of cortisol in a single scalp hair sample offers diagnostic accuracy for CS similar to currently used first-line tests, and can be used to investigate cortisol exposure in CS patients months to years back in time, enabling the estimation of disease onset.

Free access

Andrea Oßwald, Eva Plomer, Christina Dimopoulou, Monika Milian, Rainer Blaser, Katrin Ritzel, Anne Mickisch, Ferengis Knerr, Milan Stanojevic, Klaus Hallfeldt, Jochen Schopohl, Klaus A Kuhn, Günter Stalla, Felix Beuschlein, and Martin Reincke

Objective

Bilateral adrenalectomy (BADX) is an important treatment option for patients with Cushing's syndrome (CS). Our aim is to analyze the long-term outcomes, surgical, biochemical, and clinical as well as morbidity and mortality, of patients who underwent BADX.

Design

A total of 50 patients who underwent BADX since 1990 in two German centers were identified. Of them, 34 patients had Cushing's disease (CD), nine ectopic CS (ECS), and seven ACTH-independent bilateral adrenal hyperplasia (BAH).

Methods

Standardized follow-up examination was performed in 36 patients with a minimum follow-up time of 6 months after BADX and a median follow-up time of 11 years.

Results

Surgical morbidity and mortality were 6 and 4% respectively. All patients were found to be in remission after BADX. Almost all Cushing's-specific comorbidities except for psychiatric diseases improved significantly. Health-related quality of life remained impaired in 45.0% of female and 16.7% of male patients compared with a healthy population. The median number of adrenal crises per 100 patient-years was four. Nelson tumor occurred in 24% of CD patients after a median time span of 51 months. Long-term mortality after 10 years was high in ECS (44%) compared with CD (3%) and BAH (14%).

Conclusions

BADX is an effective and relatively safe treatment option especially in patients with CD. The majority of patients experience considerable improvement of Cushing's symptoms.

Free access

Daniel A Heinrich, Christian Adolf, Lars C Rump, Ivo Quack, Marcus Quinkler, Stefanie Hahner, Andrzej Januszewicz, Jochen Seufert, Holger S Willenberg, Nina Nirschl, Lisa Sturm, Felix Beuschlein, and Martin Reincke

Objective

Primary aldosteronism (PA) is the most common endocrine form of arterial hypertension. The German Conn’s Registry’s purpose is to improve treatment outcomes of PA. We assessed whether key clinical, biochemical and epidemiological characteristics of newly diagnosed PA cases have changed over time, potentially indicating a different screening and referral practice in Germany evolving from 2008 to 2016.

Design

The German Conn’s Registry is a multicenter database prospectively analyzing morbidity and long-term outcome of patients with PA.

Methods

Phenotypic changes between three year periods were calculated using Mann–Whitney U tests and Kruskal–Wallis tests for independent variables.

Results

Over three time periods from 2008 to 2016, we noted a relative decrease of unilateral PA cases (67 vs 43%). Significantly more females were diagnosed with PA (33 vs 43%). Median daily defined drug doses decreased (3.1 vs 2.0) in the presence of unchanged SBP (150 vs 150 mmHg), plasma aldosterone (199 vs 173 ng/L) and PRC (3.2 vs 3.2 U/L). Median ARR values decreased (70 vs 47 ng/U) and median potassium levels at diagnosis (3.5 vs 3.7 mmol/L) increased as the percentage of normokalemic patients (25 vs 41%), indicating milder forms of PA.

Conclusions

Our results are in accordance with an increased screening intensity for PA. We identified a trend toward diagnosing milder forms, increasingly more females and less unilateral cases of PA.

Free access

Zoran Erlic, Max Kurlbaum, Timo Deutschbein, Svenja Nölting, Aleksander Prejbisz, Henri Timmers, Susan Richter, Cornelia Prehn, Dirk Weismann, Jerzy Adamski, Andrzej Januszewicz, Martin Reincke, Martin Fassnacht, Mercedes Robledo, Graeme Eisenhofer, Felix Beuschlein, and Matthias Kroiss

Objective

Excess catecholamine release by pheochromocytomas and paragangliomas (PPGL) leads to characteristic clinical features and increased morbidity and mortality. The influence of PPGLs on metabolism is ill described but may impact diagnosis and management. The objective of this study was to systematically and quantitatively study PPGL-induced metabolic changes at a systems level.

Design

Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens in a clinically well-characterized prospective cohort study.

Methods

Analyses of metabolic profiles of plasma specimens from 56 prospectively enrolled and clinically well-characterized patients (23 males, 33 females) with catecholamine-producing PPGL before and after surgery, as well as measurement of 24-h urinary catecholamine using LC-MS/MS.

Results

From 127 analyzed metabolites, 15 were identified with significant changes before and after surgery: five amino acids/biogenic amines (creatinine, histidine, ornithine, sarcosine, tyrosine) and one glycerophospholipid (PCaeC34:2) with increased concentrations and six glycerophospholipids (PCaaC38:1, PCaaC42:0, PCaeC40:2, PCaeC42:5, PCaeC44:5, PCaeC44:6), two sphingomyelins (SMC24:1, SMC26:1) and hexose with decreased levels after surgery. Patients with a noradrenergic tumor phenotype had more pronounced alterations compared to those with an adrenergic tumor phenotype. Weak, but significant correlations for 8 of these 15 metabolites with total urine catecholamine levels were identified.

Conclusions

This first large prospective metabolomics analysis of PPGL patients demonstrates broad metabolic consequences of catecholamine excess. Robust impact on lipid and amino acid metabolism may contribute to increased morbidity of PPGL patients.