The direct measurement of hypertonic saline-stimulated plasma copeptin had greater diagnostic accuracy than the water-deprivation test in patients with hypotonic polyuria. (Funded by the Swiss National Foundation and others; ClinicalTrials.gov number, NCT01940614 .).

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Adrenal insufficiency (AI) is a life-threatening condition requiring life-long glucocorticoid (GC) substitution therapy, as well as stress adaptation to prevent adrenal crises. The number of individuals with primary and secondary adrenal insufficiency in Europe is estimated to be 20–50/100.000. A growing number of AI cases are due to side effects of GC treatment used in different treatment strategies for cancer and to immunotherapy in cancer treatment. The benefit of hormone replacement therapy is evident but long-term adverse effects may arise due to the non-physiological GC doses and treatment regimens used. Given multiple GC replacement formulations available comprising short-acting, intermediate, long-acting and novel modified-release hydrocortisone as well as subcutaneous formulations, this review offers a concise summary on the latest therapeutic improvements for treatment of AI and prevention of adrenal crises. As availability of various glucocorticoid formulations and access to expert centers across Europe varies widely, European Reference Networks on rare endocrine conditions aim at harmonizing treatment and ensure access to specialized patient care for individual case-by-case treatment decisions. To improve the availability across Europe to cost effective oral and parenteral formulations of hydrocortisone will save lives.

Objective: Treatment of symptomatic hyponatremia is not well established. European guidelines recommend bolus-wise administration of 150ml of 3% hypertonic saline. This recommendation is based, however, on low level of evidence. Design: Observational study Methods: Sixty-two consecutive hyponatremic patients admitted to the emergency department or intensive care unit of the University Hospital Wuerzburg were divided in subgroups according to treatment (150ml bolus of 3% hypertonic saline or conventional treatment), and symptom severity. Treatment target was defined as an increase in serum sodium by 5-10mEq/L within first 24h and maximum 8mEq/L during subsequent 24h. Results: 33/62 patients (53%) presented with moderate and 29/62 (47%) with severe symptoms. 36 were treated with hypertonic saline and 26 conventionally. In the hypertonic saline group serum sodium increased from 116±7 to 123±6 (24h) and 127±6mEq/L (48h) and from 121±6 to 126±5 and 129±4mEq/L in the conventional group, respectively. Overcorrection at 24h occurred more frequent in patients with severe than moderate symptoms (38% vs. 6%, p<0.05). Diuresis correlated positively with the degree of sodium overcorrection at 24h (r=0.6, p<0.01). Conventional therapies exposed patients to higher degrees of sodium fluctuations and an increased risk for insufficient sodium correction at 24h compared to hypertonic saline (RR 2.8, 95% CI 1.4-5.5). Conclusion: Sodium increase was more constant with hypertonic saline, but overcorrection rate was high, especially in severely symptomatic patients. Reducing bolus-volume and reevaluation before repeating bolus infusion might prevent overcorrection. Symptoms caused by exsiccosis can be misinterpreted as severely symptomatic hyponatremia and diuresis should be monitored.

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health crisis affecting millions of people worldwide. SARS-CoV-2 enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2) after being cleaved by the transmembrane protease serine 2 (TMPRSS2). In addition to the lung, gastrointestinal tract and kidney, ACE2 is also extensively expressed in endocrine tissues, including the pituitary and adrenal glands. Although glucocorticoids could play a central role as immunosuppressants during the cytokine storm, they can have both stimulating and inhibitory effects on immune response, depending on the timing of their administration and their circulating levels. Patients with adrenal insufficiency (AI) or Cushing’s syndrome (CS) are therefore vulnerable groups in relation to COVID-19. Additionally, patients with adrenocortical carcinoma (ACC) could also be more vulnerable to COVID-19 due to the immunosuppressive state caused by the cancer itself, by secreted glucocorticoids, and by anticancer treatments. This review comprehensively summarizes the current literature on susceptibility to and outcome of COVID-19 in AI, CS and ACC patients and emphasizes potential pathophysiological mechanisms of susceptibility to COVID-19 as well as the management of these patients in case of SARS-CoV-2. Finally, by performing an in silico analysis, we describe the mRNA expression of ACE2, TMPRSS2 and the genes encoding their co-receptors CTSB, CTSL and FURIN in normal adrenal and adrenocortical tumors (both adenomas and carcinomas).

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Objective: Endogenous hypercortisolism predisposes to impaired immune function and infections. To date, however, it is unknown whether there is a subtype-specific pattern in white blood cell (WBC) and WBC differential (WBCD) count. Methods: Retrospective monocentric cohort study in patients with overt endogenous Cushing’s syndrome (CS) or adrenal incidentalomas and autonomous cortisol secretion (ACS), with WBC/WBCD analysis at initial diagnosis and after biochemical remission. Cut-offs were obtained by receiver operating characteristics analysis. Results: 253 patients were analyzed (Cushing´s disease (CD); n=88; ectopic CS (ECS), n=31; cortisol-producing adrenal adenomas (CPA), n=40; ACS, n=45; adrenocortical carcinomas (ACC), n=49). Total leukocytes and neutrophils correlated positively with serum cortisol after 1-mg dexamethasone (r=0.314 and r=0.428), while a negative correlation was observed for lymphocytes and eosinophils (r= -0.374 and r= -0.380) (each p<0.0001). Similar observations were made for 24h-urinary free cortisol. CD and ECS differed in numbers of neutrophils and lymphocytes (p<0.0001) and were well differentiated at a cut-off of 6.1 for the neutrophil/lymphocyte ratio (NLR; sensitivity 90.0%, specificity 89.4%, AUC 0.918). For adrenocorticotropic hormone (ACTH)-independent CS, the best diagnostic outcome was obtained for the discrimination of CPA and ACC at a cut-off of 187.9 for the platelet/lymphocyte ratio (sensitivity 59.6%, specificity 80.6%, AUC 0.713). For ECS, CPA, and CD, neutrophils decreased (delta -47.0%, -29.7%, and -26.2%) and lymphocytes increased (+123.2%, +78.1%, and +17.7%) already 3 months after remission. Conclusion. Most immune cells correlate with the degree of hypercortisolism and differ among CS subtypes. WBCD changes are already identified three months after remission from endogenous hypercortisolism.

Background 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. Methods 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. Results 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. Conclusion 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.