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Free access

Robert Kopetschke, Mario Slisko, Aylin Kilisli, Ulrich Tuschy, Henri Wallaschofski, Martin Fassnacht, Manfred Ventz, Felix Beuschlein, Martin Reincke, Nicole Reisch, and Marcus Quinkler

Context

Adrenal and extra-adrenal phaeochromocytoma are chromaffin cell-derived tumours that are discovered due to classical symptom triad with headache, sweating and palpitations combined with persistent or paroxysmal hypertension. However, an increasing proportion of phaeochromocytoma seems to be discovered incidentally upon abdominal imaging.

Objective

To specify the exact circumstances of discovery of adrenal and extra-adrenal phaeochromocytoma.

Design and patients

Four German endocrine centres participated in this retrospective study. Medical records of 201 patients with adrenal and extra-adrenal phaeochromocytoma who were diagnosed between 1973 and 2007 were analyzed.

Results

The typical triad of symptoms was found only in 10% of cases. Ten percent of patients presented were without clinical symptoms and 6.1% were normotensive. Documented blood pressure peaks occurred in 44.1% of cases. In 24 patients (12.2%), phaeochromocytoma was malignant. Before 1985, <10% of cases were incidentally discovered, whereas thereafter the frequency was >25% (29.4% of the total study population). Patients with incidentally detected phaeochromocytoma were significantly older (53.1±1.9 vs 47.0±1.3 years; P<0.05) and often had less blood pressure peaks (37.0 vs 70.7%; P<0.001) than patients in whom the diagnosis was suspected on clinical grounds. Of phaeochromocytomas 94.4% were intra-adrenal tumours, of which 12.9% were bilateral. Bilateral tumours were significantly smaller than unilateral tumours (36.6±14.7 vs 52.5±34.3 mm; P<0.05), whereas extra-adrenal tumours had a mean diameter of 52.6±28.7 mm.

Conclusions

Owing to better availability and accessibility of imaging procedures, the number of incidentally discovered phaeochromocytoma is increasing and reaches nearly 30% in our study population. Every adrenal incidentaloma should be investigated for the presence of phaeochromocytoma.

Free access

Andrea Oßwald, Evelyn Fischer, Christoph Degenhart, Marcus Quinkler, Martin Bidlingmaier, Anna Pallauf, Katharina Lang, Thomas Mussack, Klaus Hallfeldt, Felix Beuschlein, and Martin Reincke

Objective

Adrenal vein sampling (AVS) is a technically demanding procedure required for the identification of suitable candidates for unilateral adrenalectomy in primary aldosteronism. Recently, somatic KCNJ5 K+-channel mutations in aldosterone-producing adenoma (APA) patients have been shown to influence steroid gradients during AVS. These and other recently identified genetic modifiers (ATP1A1 and ATP2B3) might affect the final diagnosis and treatment of the affected patients.

Design

Fifty-nine patients with APAs who had undergone successful AVS (adrenal vein cortisol:peripheral cortisol ratio ≥2) and had undergone a mutation analysis of their tumor tissue were studied. The mutation status of the APAs was as follows: 19 KCNJ5 mutations, eight ATPase mutations (five ATP1A1 and three ATP2B3), and 32 patients with none of these mutations.

Methods

The lateralization index (ratio of aldosterone:cortisol on the side of the adenoma to aldosterone to cortisol on the contralateral side) and the contralateral suppression index (ratio of aldosterone:cortisol on the contralateral side to aldosterone to cortisol in the periphery) were calculated for the KCNJ5-mutated, ATPase-mutated, and the KCNJ5/ATPase mutation-negative APA patients.

Results

The lateralization indices of the ATPase mutation carriers had a median of 19.9 compared with a median of 16.0 in the KCNJ5 mutation carriers and that of 20.5 in the KCNJ5/ATPase mutation-negative patients. The contralateral suppression indices of the ATPase-mutated patients had a median of 0.1 compared with a median of 0.4 in the KCNJ5 mutation carriers and that of 0.2 in the KCNJ5/ATPase mutation-negative patients. The differences between the genetic groups were not statistically significant.

Conclusions

We did not find evidence for a clinically important impact of mutation status on steroid gradients during AVS.

Free access

Katrin Ritzel, Felix Beuschlein, Christina Berr, Andrea Osswald, Nicole Reisch, Martin Bidlingmaier, Harald Schneider, Jürgen Honegger, Lucas L. Geyer, Jochen Schopohl, and Martin Reincke

Objective

The aim of the present study was to validate criteria of corticotropin-releasing hormone (CRH) stimulation and 8 mg dexamethasone suppression (high-dose dexamethasone suppression, HDDS) to distinguish the etiology of ACTH-dependent Cushing's syndrome.

Subjects and methods

We retrospectively analyzed cortisol and ACTH after the injection of 100 μg human CRH in confirmed Cushing's disease (CD, n=78) and confirmed ectopic Cushing's syndrome (ECS, n=18). Cortisol and ACTH increase (in percentage above basal (%B)) at each time point, maximal increase (Δmax %B), and area under the curve (AUC %B) were analyzed using receiver operator characteristics (ROC) curve analyses. Cortisol suppression (%B) after 8 mg of dexamethasone was evaluated as a supplementary criterion.

Results

An increase in ACTH of ≥43%B at 15 min after CRH was the strongest predictor of CD, with a positive likelihood ratio of 14.0, a sensitivity of 83%, a specificity of 94%, a positive predictive value of 98% and a negative predictive value of 58%. All of the other criteria of stimulated ACTH and cortisol levels were not superior in predicting CD in response to CRH injection. The addition of cortisol suppression by dexamethasone did not increase the discriminatory power. However, the combination of a positive ACTH response at 15 min and a positive HDDS test excluded ECS in all cases.

Conclusion

The present findings support the use of plasma ACTH levels 15 min after the injection of human CRH as a response criterion for distinguishing between CD and ECS. The addition of the HDDS test is helpful for excluding ECS when both tests are positive.

Free access

Marianne Weigel, Anna Riester, Gregor Hanslik, Katharina Lang, Holger S Willenberg, Stephan Endres, Bruno Allolio, Felix Beuschlein, Martin Reincke, and Marcus Quinkler

Objective

The saline infusion test (SIT) is widely used as a confirmatory test for primary aldosteronism (PA). SIT results are judged as follows: post-test aldosterone levels <50 ng/l exclude PA, whereas levels >50 ng/l confirm PA. We hypothesized that post-SIT aldosterone concentrations indicate the severity of PA and might predict outcome.

Design

The study includes 256 PA patients of the German Conn's Registry who prospectively underwent SIT. The data of 126 patients with complete follow-up of 1.2±0.3 years after diagnosis were analyzed. The patients were divided into two groups with post-SIT aldosterone levels of 50–100 ng/l (group 1; n=38) and of >100 ng/l (group 2; n=88).

Results

Patients in group 2 had a significantly shorter duration of hypertension (7.5 vs 11.7 years (median), P=0.014), higher systolic blood pressure (BP; 151±16 vs 143±17 mmHg, P=0.036), lower serum potassium (3.3±0.6 vs 3.5±0.4 mmol/l, P=0.006), higher 24-h urine protein excretion (7.4 vs 5.4 mg/dl (median), P=0.012), and were more often female (P=0.038). They showed more often unilateral disease (P<0.005) with larger tumors (14±10 vs 7±10 mm, P=0.021), underwent more often adrenalectomy (75% vs 37%, P<0.005), required a lower number of antihypertensive drugs after adrenalectomy (1.2±1.2 vs 2.5±1.4, P=0.001), had a faster normalization of urinary protein excretion (with medical treatment P=0.049; with Adx P<0.005) at follow-up, and more frequently underlying well-characterized mutation (P=0.047).

Conclusions

PA patients with post-SIT aldosterone levels of >100 ng/l have a more rapid development of PA caused more frequently by unilateral disease with larger aldosterone-producing adenomas. However, this group of patients may have a significantly better outcome following specific treatment.

Free access

Anna Riester, Dirk Weismann, Marcus Quinkler, Urs D Lichtenauer, Sandra Sommerey, Roland Halbritter, Randolph Penning, Christine Spitzweg, Jochen Schopohl, Felix Beuschlein, and Martin Reincke

Objective

Pheochromocytomas are rare chromaffin cell-derived tumors causing paroxysmal episodes of headache, palpitation, sweating and hypertension. Life-threatening complications have been described in case reports and small series. Systematic analyses are not available. We took an opportunity of a large series to make a survey.

Design and methods

We analyzed records of patients diagnosed with pheochromocytomas in three geographically spread German referral centers between 2003 and 2012 (n=135).

Results

Eleven percent of the patients (ten women, five men) required in-hospital treatment on intensive care units (ICUs) due to complications caused by unsuspected pheochromocytomas. The main reasons for ICU admission were acute catecholamine induced Tako-Tsubo cardiomyopathy (n=4), myocardial infarction (n=2), acute pulmonary edema (n=2), cerebrovascular stroke (n=2), ischemic ileus (n=1), acute renal failure (n=2), and multi organ failure (n=1). One patient required extracorporeal membrane oxygenation due to a hypertensive crisis with lung edema occurring during delivery (n=1). Two patients died of refractory shock and pheochromocytomas were found postmortem. Two patients were treated by emergency surgery. Compared to pheochromocytoma patients without life-threatening events (n=120), patients with complications had a significant larger maximal tumor diameter (7.0 vs 4.5 cm, P<0.01), higher levels of catecholamines (20- vs ninefold upper limit of normal, P<0.01), and tended to be younger (42 vs 51 years, P=0.05).

Conclusion

Although pheochromocytomas are rare, they are likely to be associated with a life-threatening situation. Clinicians have to be aware of these situations and perform a timely diagnosis.

Free access

Benjamin Lechner, Katharina Lechner, Daniel Heinrich, Christian Adolf, Finn Holler, Holger Schneider, Felix Beuschlein, and Martin Reincke

In patients with primary aldosteronism, specific treatment provides prognostic benefit over optimal antihypertensive therapy and is therefore crucial to reduce mortality and morbidity in this subgroup of patients with hypertension. Prognostic relevance has been shown for adrenalectomy in unilateral disease and for medical treatment with mineralocorticoid receptor antagonists in bilateral adrenal hyperplasia. Collectively, evidence points to the superiority of surgical treatment compared to medical treatment. The causal approach of removing the mineralocorticoid excess, as well as the often-accompanying glucocorticoid excess, might provide one biologically plausible explanation for the observation of slightly better outcomes with surgical therapy. However, in patients living with primary aldosteronism, medical treatment is often insufficient for three major reasons. First and foremost, no marker of sufficient aldosterone blockade has yet been established and therefore adequate treatment of the aldosterone excess is often dismissed as a treatment goal. Second, side effects often limit patient compliance. Third, as recommendations differ from other indications like heart failure, drug dosing is often inadequate. The aim of this review is first to provide an overview over medical treatment options and second to review potential markers for treatment surveillance in patients with primary aldosteronism.

Free access

Anke Hannemann, Christa Meisinger, Martin Bidlingmaier, Angela Döring, Barbara Thorand, Margit Heier, Petra Belcredi, Karl-Heinz Ladwig, Henri Wallaschofski, Nele Friedrich, Sabine Schipf, Jan Lüdemann, Rainer Rettig, Jörg Peters, Henry Völzke, Jochen Seissler, Felix Beuschlein, Matthias Nauck, and Martin Reincke

Objective

The aim of this study was to analyze the potential association of the plasma aldosterone concentration (PAC) with the metabolic syndrome (MetS) and its components in two German population-based studies.

Methods

We selected 2830 and 2901 participants (31–80 years) from the follow-ups of the Study of Health in Pomerania (SHIP)-1 and the Cooperative Health Research in the Region of Augsburg (KORA) F4 respectively. MetS was defined as the presence of at least three out of the following five criteria: waist circumference ≥94 cm (men (m)) and ≥80 cm (women (w)); high-density lipoprotein (HDL) cholesterol <1.0 mmol/l (m) and <1.3 mmol/l (w); blood pressure ≥130/85 mmHg or antihypertensive treatment; non-fasting glucose (SHIP-1) ≥8 mmol/l, fasting glucose (KORA F4) ≥5.55 mmol/l or antidiabetic treatment; non-fasting triglycerides (SHIP-1) ≥2.3 mmol/l, fasting triglycerides (KORA F4) ≥1.7 mmol/l, or lipid-lowering treatment. We calculated logistic regression models by comparing the highest study- and sex-specific PAC quintiles versus all lower quintiles.

Results

MetS was common with 48.1% (m) and 34.8% (w) in SHIP-1 and 42.7% (m) and 27.5% (w) in KORA F4. Our logistic regression models revealed associations of PAC with MetS, elevated triglycerides, and decreased HDL cholesterol in SHIP-1 and KORA F4.

Conclusions

Our findings add to the increasing evidence supporting a relation between aldosterone and MetS and suggest that aldosterone may be involved in the pathophysiology of MetS and lipid metabolism disorders.

Free access

Charlotte Michaela Fries, Yoon Ju Bae, Nada Rayes, Benjamin Sandner, Berend Isermann, Michael Stumvoll, Valentina Fagotto, Martin Reincke, Martin Bidlingmaier, Vogel Mandy, Jürgen Kratzsch, and Wiebke Kristin Fenske

Objective

Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has become state of the art for the quantitative analysis of steroid hormones. Although method comparisons show that aldosterone measurement using LC-MS/MS yields considerably lower levels than immunoassays (IAs), method-specific cutoff values for primary aldosteronism (PA) are largely missing. Objective of this study was to analyze the diagnostic accuracy of proposed LC-MS/MS-specific cutoff values for the saline infusion test (SIT).

Design and methods

From 2016 to 2019, 104 consecutive patients suspected of PA underwent the SIT and captopril challenge test in the tertiary medical center at the University Hospital of Leipzig, Germany. Patients with positive case confirmation underwent adrenal imaging and adrenal venous sampling for subtype classification.

Results

Overall, proposed assay-specific PACLC-MS/MS cutoff values for the SIT achieved higher diagnostic accuracy than established PACIA values with a sensitivity and specificity of 87.5% (95% CI: 71.0–96.5) and 97% (95% CI: 89.6–99.6) for a cutoff of 120 pmol/L and 93.8% (95% CI: 79.2–99.2) and 92.5% (95% CI: 83.4–97.5) for a cutoff of 94 pmol/L. The most accurate post-SIT PACLC-MS/MS cutoff value in this study was 83 pmol/L, yielding a sensitivity and specificity of 96.9% (95% CI: 83.8–99.9) and 92.5% (95% CI: 83.4–97.5), respectively.

Conclusions

The present data confirm the need for the implication of lower method-specific aldosterone cutoff values for the diagnosis of PA with LC-MS/MS based aldosterone measurement.

Free access

Cristina L Ronchi, Erika Peverelli, Sabine Herterich, Isabel Weigand, Giovanna Mantovani, Thomas Schwarzmayr, Silviu Sbiera, Bruno Allolio, Jürgen Honegger, Silke Appenzeller, Andrea G Lania, Martin Reincke, Davide Calebiro, Anna Spada, Michael Buchfelder, Joerg Flitsch, Tim M Strom, and Martin Fassnacht

Context

Alterations in the cAMP signaling pathway are common in hormonally active endocrine tumors. Somatic mutations at GNAS are causative in 30–40% of GH-secreting adenomas. Recently, mutations affecting the USP8 and PRKACA gene have been reported in ACTH-secreting pituitary adenomas and cortisol-secreting adrenocortical adenomas respectively. However, the pathogenesis of many GH-secreting adenomas remains unclear.

Aim

Comprehensive genetic characterization of sporadic GH-secreting adenomas and identification of new driver mutations.

Design

Screening for somatic mutations was performed in 67 GH-secreting adenomas by targeted sequencing for GNAS, PRKACA, and USP8 mutations (n=31) and next-generation exome sequencing (n=36).

Results

By targeted sequencing, known activating mutations in GNAS were detected in five cases (16.1%), while no somatic mutations were observed in both PRKACA and USP8. Whole-exome sequencing identified 132 protein-altering somatic mutations in 31/36 tumors with a median of three mutations per sample (range: 1–13). The only recurrent mutations have been observed in GNAS (31.4% of cases). However, seven genes involved in cAMP signaling pathway were affected in 14 of 36 samples and eight samples harbored variants in genes involved in the calcium signaling or metabolism. At the enrichment analysis, several altered genes resulted to be associated with developmental processes. No significant correlation between genetic alterations and the clinical data was observed.

Conclusion

This study provides a comprehensive analysis of somatic mutations in a large series of GH-secreting adenomas. No novel recurrent genetic alterations have been observed, but the data suggest that beside cAMP pathway, calcium signaling might be involved in the pathogenesis of these tumors.

Restricted access

Frederick Vogel, Leah Braun, German Rubinstein, Stephanie Zopp, Sarina Benedix, Holger Schneider, Katrin Ritzel, Katharina Schilbach, Ralf Schmidmaier, Felix Beuschlein, Martin Bidlingmaier, and Martin Reincke

Background

Glucocorticoid excess leads to muscle atrophy and weakness in patients with endogenous Cushing’s syndrome. Insulin-like growth factor I (IGF-I) is known to have protective effects on muscle loss. We hypothesized that individual serum IGF-I concentrations might be predictive for long-term myopathy outcome in Cushing’s syndrome.

Patients and methods

In a prospective longitudinal study of 31 patients with florid Cushing’s syndrome, we analyzed IGF-I and IGF binding protein 3 (IGFBP 3) concentrations at the time of diagnosis and following surgical remission over a period of up to 3 years. We assessed muscle strength by grip strength measurements using a hand grip dynamometer and muscle mass by bio-impedance measurements.

Findings

Individual serum IGF-I concentrations in the postoperative phase were strongly predictive of long-term grip strength outcome (rs = 0.696, P ≤ 0.001). Also, lower IGF-I concentrations were associated with a lower muscle mass after 3 years (rs = 0.404, P  = 0.033). While patients with high IGF-I s.d. scores (SDS; >1.4) showed an improvement in grip strength within the follow-up period (P  = 0.009), patients with lower IGF-I SDS (≤−0.4) had a worse outcome with persisting muscle dysfunction. In contrast, preoperative IGF-I concentrations during the florid phase of Cushing’s syndrome did not predict long-term muscle function outcome (rs = 0.285, P  = 0.127).

Conclusion

Lower individual IGF-I concentrations 6 months after curative surgery for Cushing’s syndrome are associated with adverse long-term myopathy outcome and IGF-I might be essential for muscle regeneration in the early phase after correction of hypercortisolism.