Diabetes insipidus (DI), be it from central or nephrogenic origin, must be differentiated from secondary forms of hypotonic polyuria such as primary polydipsia. Differentiation is crucial since wrong treatment can have deleterious consequences. Since decades, the gold standard for differentiation has been the water deprivation test, which has limitations leading to an overall unsatisfying diagnostic accuracy. Furthermore, it is cumbersome for patients with a long test duration. Clinical signs and symptoms and MRI characteristics overlap between patients with DI and primary polydipsia. The direct test including vasopressin (AVP) measurement upon osmotic stimulation was meant to overcome these limitations, but failed to enter clinical practice mainly due to technical constraints of the AVP assay. Copeptin is secreted in equimolar amount to AVP but can easily be measured with a sandwich immunoassay. A high correlation between copeptin and AVP has been shown. Accordingly, copeptin mirrors the amount of AVP in the circulation and has led to a ‘revival’ of the direct test in the differential diagnosis of DI. We have shown that a baseline copeptin, without prior thirsting, unequivocally identifies patients with nephrogenic DI. In contrast, for the differentiation between central DI and primary polydipsia, a stimulated copeptin level of 4.9 pmol/L upon hypertonic saline infusion differentiates these two entities with a high diagnostic accuracy and is superior to the water deprivation test. Close sodium monitoring during the test is a prerequisite. Further new test methods are currently evaluated and might provide an even simpler way of differential diagnosis in the future.
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.
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.
Julie Refardt, Clara Odilia Sailer, Irina Chifu, Bettina Winzeler, Ingeborg Schnyder, Martin Fassnacht, Wiebke Fenske, Mirjam Christ-Crain and the CODDI-Investigators
Diagnosis and treatment of dysnatremia is challenging and further complicated by the pitfalls of different sodium measurement methods. Routinely used sodium measurements are the indirect (plasma/serum) and direct (whole blood) ion-selective electrode (ISE) method, showing discrepant results especially in the setting of acute illness. Few clinicians are aware of the differences between the methods in clinically stable patients or healthy volunteers.
Data of 140 patients and 91 healthy volunteers undergoing osmotic stimulation with hypertonic saline infusion were analyzed. Sodium levels were measured simultaneously by indirect and direct ISE method before and at different time points during osmotic stimulation up to a sodium threshold of ≥150 mmol/L. The primary outcome was the difference in sodium levels between the indirect and direct ISE method.
878 sodium measurements were analyzed. Mean (s.d.) sodium levels ranged from 141 mmol/L (2.9) to 151 mmol/L (2.1) by the indirect ISE compared to 140 mmol/L (3) to 149 mmol/L (2.8) by the direct ISE method. The interclass correlation coefficient between the two methods was 0.844 (95% CI: 0.823–0.863). On average, measurements by the indirect ISE were 1.9 mmol/L (95% CI limits: −3.2 to 6.9) higher than those by the direct ISE method (P < 0.001). The tendency of the indirect ISE method resulting in higher levels increased with increasing sodium levels.
Intra-individual sodium levels differ significantly between the indirect and direct ISE method also in the absence of acute illness. It is therefore crucial to adhere to the same method in critical situations to avoid false decisions due to measurement differences.
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.