Stefanie Neidert, Philipp Schuetz, Beat Mueller and Mirjam Christ-Crain
Suppression of the adrenal function after glucocorticoid treatment is common, potentially dangerous, and unpredictable. Identification of patients at risk is of clinical importance. We hypothesized that the dexamethasone suppression test predicts the development of corticosteroid-induced impaired adrenal function.
We included 39 healthy male volunteers. After a 1-μg ACTH test, all participants underwent an overnight 0.5-mg dexamethasone suppression test. Participants then took prednisone, 0.5 mg/kg body weight, for 14-day. After the withdrawal of prednisone, a 1-μg ACTH test was performed and a clinical score was assessed on days 1, 3, 7, and 21.
On days 1, 3, 7, and 21, 100, 50, 26.5 and 32.4% of the participants had a suppressed adrenal function. The risk of developing suppressed adrenal function decreased from 44 to 0% in patients with cortisol levels after the administration of dexamethasone in the lowest and highest quartiles respectively. Receiver operating curve (ROC) analysis performed to predict a suppressed adrenal function on day 7 after the withdrawal of prednisone showed an area under the curve (AUC) of 0.76 (95% confidence interval (CI) 0.58–0.89) for cortisol after the administration of dexamethasone, which was in the range of the AUC of 0.78 (95% CI 0.6–0.9) for pre-intervention cortisol after the administration of ACTH. Basal cortisol before intake of prednisone (AUC 0.62 (95% CI 0.44–0.78)) and the clinical score (AUC 0.64 (95% CI 0.45–0.79)) had significantly lower AUCs.
Circulating cortisol levels after a dexamethasone suppression test and a pre-intervention-stimulated cortisol level are predictive of later development of a suppressed adrenal function after a 14-day course of prednisone, and are superior to a clinical score or basal cortisol levels. This may allow a more targeted concept for the need of stress prophylaxis after cessation of steroid therapy.
Judith Siegenthaler, Carla Walti, Sandrine Andrea Urwyler, Philipp Schuetz and Mirjam Christ-Crain
The prognostic/diagnostic biomarker copeptin, an arginine vasopressin surrogate, reflects physical stress. Whether copeptin concentration increases upon psychological stress is unknown. We investigated psychological stress effects on copeptin secretion in healthy volunteers and patients with central diabetes insipidus (DI).
A prospective observational study was conducted to study the relation between copeptin concentration and psychological stress.
A total of 20 healthy adults (ten female) and eight patients with central DI (four female) underwent the Trier Social Stress Test including, in order, 30-min waiting period, 10-min anticipation period, 10-min test period and 40-min recovery. Serum copeptin and cortisol concentrations and self-rated stress component feelings were determined in the pre-/post-anticipation period, post-test period and twice post-recovery.
In healthy volunteers, the median (25th–75th percentile) copeptin concentration peaked immediately during the post-test period at 5.1 (3.2–7.0) pmol/l, vs 3.7 (2.6–5.4) pmol/l at baseline. Over the measurement course, copeptin concentration significantly elevated (coefficient; 95% CI) (0.14; 0.06–0.23, P=0.002). The important predictors of increase in copeptin concentration were feelings of tension (0.06; 0.04–0.08, P<0.001) and avoidance (0.07; 0.04–0.10; P<0.001). Copeptin and cortisol levels were associated (0.43; 0.13–0.72, P<0.005). Patients with DI had lower baseline concentrations (1.55 (1.2–3.1) pmol/l) when compared with healthy volunteers, P=0.006. Patients with DI showed no increase upon psychological stress (peak 2.15 pmol/l (1.5–2.28), P=0.79). By contrast, cortisol values were similar in patients and volunteers.
In healthy volunteers, copeptin levels significantly increased after psychological stress testing; this response was blunted in patients with DI.
Philipp Schuetz, Beat Müller, Charly Nusbaumer, Melanie Wieland and Mirjam Christ-Crain
Circulating levels of GH are increased during critical illness and correlate with outcome in children with meningococcal sepsis. We assessed the prognostic implications of GH on admission and during follow-up in critically ill adult patients admitted to a medical intensive care unit.
Materials and methods
We measured GH, IGF1 and IGF-binding protein3 (IGFBP-3) plasma concentrations in 103 consecutive critically ill patients and compared it with two clinical severity scores (APACHE II, SAPS II).
Median GH levels on admission were similar in septic (n=53) and non-septic (n=50) patients and about 7-fold increased in the 24 non-survivors as compared with survivors (9.50 (interquartile ranges (IQR) 3.53–18.40) vs 1.4 (IQR 0.63–5.04), P<0.0001). GH levels increased with increasing severity of sepsis (sepsis, severe sepsis, and septic shock, P=0.019). By contrast, IGF1 and IGFBP-3 did not correlate with severity of disease or mortality. Logistic regression models showed that GH and both clinical scores were independent predictors of mortality with a similar prognostic accuracy (GH: area under the curve (AUC) 0.81 (95% confidence interval (CI), 0.71–0.92), APACHE II: AUC 0.71 (95% CI, 0.58–0.83), P=0.16, SAPS II: AUC 0.75 (95% CI, 0.63–0.86, P=0.36)). GH improved the prognostic accuracy of the APACHE II score to an AUC of 0.78 (95% CI, 0.66–090, P=0.04) and tended to improve the SAPS II score to an AUC of 0.79 (95% CI, 0.67–0.90, P=0.09).
GH plasma concentrations on admission are independent predictors for mortality in adult critically ill patients and may complement existing risk prediction scores, namely the APACHE II and the SAPS II score.
Tristan Struja, Hannah Fehlberg, Alexander Kutz, Larissa Guebelin, Christian Degen, Beat Mueller and Philipp Schuetz
Identification of pretreatment risk factors predicting relapse in patients with hyperthyroidism of Graves’ disease after stopping anti-thyroid drugs (ATD) is decisive to guide therapeutic options.
We performed a systematic search and meta-analysis to study predictors for relapse after stopping ATD in patients with Graves’ disease.
Based on a pre-specified protocol, we searched PubMed, EMBASE and Cochrane in July 2015 for case–control, controlled and randomized-controlled trials reporting risk factors for relapse after stopping ATD. The primary endpoint was relapse of disease until follow-up. PRISMA and SIGN statements were used for reviewing the data and assessing the quality of included trials.
We included 54 trials with a total of 7595 participants. Most trials were small with moderate-to-high risk for bias. Ten trials were assessed only qualitatively (2227 patients), genomic data were reported in 13 trials (2178 patients) and 31 trials (4346 patients) were assessed quantitatively. In total, there were 3696 relapses in 7595 patients (48.7%). By using random-effects meta-analysis, orbitopathy, smoking, thyroid volume measured by sonography, goiter size, fT4, tT3, TRAb and TBII were significantly associated with relapse, whereas male vs female sex, age and initial tT4 level did not show significant associations.
This analysis found several risk factors to predict relapse in Graves’ disease, which can be combined in a risk score. Prospective studies should evaluate the prognostic accuracy of such a score to guide treatment decisions.
Eleonora Seelig, Stefanie Meyer, Katharina Timper, Nicole Nigro, Martina Bally, Ida Pernicova, Philipp Schuetz, Beat Müller, Marta Korbonits and Mirjam Christ-Crain
Patients receiving glucocorticoid treatment are prone to develop metabolic complications. In preclinical studies, metformin prevented the development of the metabolic syndrome during glucocorticoid excess. We herein investigated the metabolic effect of metformin during glucocorticoid treatment in non-diabetic patients.
In a double-blind, placebo-controlled trial, patients starting glucocorticoid treatment (prednisone, prednisolone or methylprednisolone) for four weeks were randomised to concomitantly receive metformin (850 mg once daily for one week followed by 850 mg twice daily for three weeks) or placebo. All patients underwent a standardised oral glucose tolerance test at baseline and after four weeks. The primary endpoint was change in the 2-h area under the curve (AUC) of glucose during the oral glucose tolerance test between baseline and four weeks.
29 of 34 randomised non-diabetic patients completed the trial (17 metformin and 12 placebo). In patients allocated to placebo, median glucose 2-h AUC increased from baseline to four weeks (836 (IQR 770–966) to 1202 (1009–1271) mmol/L per min; P = 0.01). In contrast, glucose levels remained similar to baseline in the metformin group (936 (869–1003) to 912 (825–1011) mmol/L per min; P = 0.83). This change within four weeks was different between both groups (P = 0.005). Glucocorticoid equivalent doses were similar in both groups (placebo: 980.0 (560.0–3259.8) mg/28 days; metformin: 683.0 (437.5–1970.5) mg/28 days; P = 0.26).
In this first randomised controlled trial of metformin targeting metabolic complications in patients needing glucocorticoid therapy, we observed a beneficial effect of metformin on glycaemic control. Metformin thus seems to be a promising drug for preventing metabolic side effects during systemic glucocorticoid treatment.
Bettina Winzeler, Nica Jeanloz, Nicole Nigro, Isabelle Suter-Widmer, Philipp Schuetz, Birsen Arici, Martina Bally, Claudine Blum, Andreas Bock, Andreas Huber, Beat Mueller and Mirjam Christ-Crain
Hyponatremia is the most common electrolyte abnormality in hospitalized patients and given its impact on mortality and morbidity, a relevant medical condition. Nevertheless, little is known about factors influencing long-term outcome.
This is a prospective observational 12-month follow-up study of patients with profound hyponatremia (≤125 mmol/L) admitted to the emergency department of two tertiary care centers between 2011 and 2013. We analyzed the predictive value of clinical and laboratory parameters regarding the following outcomes: 1-year mortality, rehospitalization and recurrent profound hyponatremia.
Median (IQR) initial serum sodium (s-sodium) level of 281 included patients was 120 mmol/L (116–123). During the follow-up period, 58 (20.6%) patients died. The majority (56.2%) were rehospitalized at least once. Recurrent hyponatremia was observed in 42.7%, being profound in 16%. Underlying comorbidities, assessed by the Charlson Comorbidity Index, predicted 1-year mortality (odds ratio (OR) 1.43, 95% confidence interval (CI) 1.25–1.64, P < 0.001). Furthermore, ‘s-sodium level at admission’ (OR 1.14, 95% CI 1.01–1.29, P = 0.036) and ‘correction of hyponatremia’ defined as s-sodium ≥135 mmol/L at discharge were associated with mortality (OR 0.47, 95% CI 0.23–0.94, P = 0.034). Mortality rate fell with decreasing baseline s-sodium levels and was lower in the hyponatremia category ≤120 mmol/L vs >120 mmol/L (14.8% and 27.8%, P < 0.01). Patients with s-sodium level ≤120 mmol/L were more likely to have drug-induced hyponatremia, whereas hypervolemic hyponatremia was more common in patients with s-sodium >120 mmol/L.
Hyponatremia is associated with a substantial 1-year mortality, recurrence and rehospitalization rate. The positive correlation of s-sodium and mortality emphasizes the importance of the underlying disease, which determines the outcome besides hyponatremia itself.
Tristan Struja, Marina Kaeslin, Fabienne Boesiger, Rebecca Jutzi, Noemi Imahorn, Alexander Kutz, Luca Bernasconi, Esther Mundwiler, Beat Mueller, Mirjam Christ-Crain, Fabian Meienberg, Fahim Ebrahimi, Christoph Henzen, Stefan Fischli, Marius Kraenzlin, Christian Meier and Philipp Schuetz
First-line treatment in Graves’ disease is often done with antithyroid agents (ATD), but relapse rates remain high making definite treatment necessary. Predictors for relapse risk help guiding initial treatment decisions.
We aimed to externally validate the prognostic accuracy of the recently proposed Graves’ Recurrent Events After Therapy (GREAT) score to predict relapse risk in Graves’ disease.
Design, setting and participants
We retrospectively analyzed data (2004–2014) of patients with a first episode of Graves’ hyperthyroidism from four Swiss endocrine outpatient clinics.
Main outcome measures
Relapse of hyperthyroidism analyzed by multivariate Cox regression.
Of the 741 included patients, 371 experienced a relapse (50.1%) after a mean follow-up of 25.6 months after ATD start. In univariate regression analysis, higher serum free T4, higher thyrotropin-binding inhibitor immunoglobulin (TBII), younger age and larger goiter were associated with higher relapse risk. We found a strong increase in relapse risk with more points in the GREAT score from 33.8% in patients with GREAT class I (0–1 points), 59.4% in class II (2–3 points) with a hazard ratio of 1.79 (95% CI: 1.42–2.27, P < 0.001) and 73.6% in class III (4–6 points) with a hazard ratio of 2.24 (95% CI: 1.64–3.06, P < 0.001).
Based on this retrospective analysis within a large patient population from a multicenter study, the GREAT score shows good external validity and can be used for assessing the risk for relapse in Graves’ disease, which influence the initial treatment decisions.
Philipp Schuetz, Jörg D Leuppi, Roland Bingisser, Michael Bodmer, Matthias Briel, Tilman Drescher, Ursula Duerring, Christoph Henzen, Yolanda Leibbrandt, Sabrina Maier, David Miedinger, Beat Mueller, Andreas Scherr, Christian Schindler, Rolf Stoeckli, Sebastien Viatte, Christophe von Garnier, Michael Tamm and Jonas Rutishauser
To analyze prospectively the hypothalamic–pituitary–adrenal (HPA) axis and clinical outcome in patients treated with prednisone for exacerbated chronic obstructive pulmonary disease (COPD).
Prospective observational study.
Subjects and methods
Patients presenting to the emergency department were randomized to receive 40 mg prednisone daily for 5 or 14 days in a placebo-controlled manner. The HPA axis was longitudinally assessed with the 1 μg corticotropin test and a clinical hypocortisolism score at baseline, on day 6 before blinded treatment, at hospital discharge, and for up to 180 days of follow-up. Prednisone was stopped abruptly, irrespective of the test results. Patients discharged with pathological test results received instructions about emergency hydrocortisone treatment.
A total of 311 patients were included in the analysis. Mean basal and stimulated serum total cortisol levels were highest on admission (496±398 and 816±413 nmol/l respectively) and lowest on day 6 (235±174 and 453±178 nmol/l respectively). Pathological stimulation tests were found in 63, 38, 9, 3, and 2% of patients on day 6, at discharge, and on days 30, 90, and 180 respectively, without significant difference between treatment groups. Clinical indicators of hypocortisolism did not correlate with stimulation test results, but cortisol levels were inversely associated with re-exacerbation risk. There were no hospitalizations or deaths as a result of adrenal crisis.
Dynamic changes in the HPA axis occur during and after the treatment of acute exacerbations of COPD. In hypocortisolemic patients who were provided with instructions about stress prophylaxis, the abrupt termination of prednisone appeared safe.
Fahim Ebrahimi, Andrea Widmer, Ulrich Wagner, Beat Mueller, Philipp Schuetz, Mirjam Christ-Crain and Alexander Kutz
Adrenal insufficiency in the outpatient setting is associated with excess morbidity, mortality, and impaired quality of life. Evidence on its health-care burden in medical inpatients is scarce. The aim of this study was to assess the health-care burden of primary adrenal insufficiency (PAI) and secondary adrenal insufficiency (SAI) among hospitalized inpatients.
Design and methods
In this nationwide cohort study, adult medical patients with either PAI or SAI hospitalized between 2011 and 2015 were compared with propensity-matched (1:1) medical controls, respectively. The primary outcome was 30-day all-cause in-hospital mortality. Main secondary outcomes included ICU admission rate, length-of-hospital stay, 30-day and 1-year all-cause readmission rates.
In total, 594 hospitalized cases with PAI and 4880 cases with SAI were included. Compared with matched controls, in-hospital mortality was not increased among PAI or SAI patients, respectively. Patients with adrenal insufficiency were more likely to be admitted to ICU (PAI: OR 1.9 (95% CI, 1.27 to 2.72) and SAI: OR 1.5 (95% CI, 1.35 to 1.75)). Length of hospital stay was prolonged by 1.0 days in PAI patients (8.9 vs 7.9 days (95% CI, 0.06 to 1.93)), and by 3.3 days in SAI patients (12.1 vs 8.8 days (95% CI, 2.82 to 3.71)), when compared with matched controls. Patients with SAI were found to have higher 30-day and 1-year readmission rates (14.1 vs 12.1% and 50.0 vs 40.7%; P < 0.001) than matched controls.
While no difference in in-hospital mortality was found, adrenal insufficiency was associated with prolonged length of hospital stay, and substantially higher rates of ICU admission and hospital readmission.