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Background: Salivary cortisol (sa-cortisol) and salivary cortisone (sa-cortisone) correlate well with serum cortisol (s-cortisol) but validated reference ranges for healthy individuals are lacking., Objective: To establish cutoff levels for sa-cortisol and cortisone following cosyntropin testing, and assess their diagnostic utility in adrenal insufficiency (AI)., Methods: Steroids in saliva were assayed using liquid-chromatography tandem-mass-spectrometry (LCMS/MS) before and after administration of 250µg cosyntropin test in 128 healthy subjects (16 on oral estrogens) and 59 patients with suspected AI, of whom 26 were diagnosed with AI with conventional serum cortisol criteria. The cutoff level for AI was defined as the 2.5th centile in healthy subjects not receiving estrogens. Performance was evaluated by calculating diagnostic accuracy and analyzing receiver operating characteristic-curves., Results: The sa-cortisol cutoff 60 minutes after cosyntropin stimulation was 12.6 nmol/L (accuracy 89%, sensitivity 85%, and specificity 90%). Sa-cortisone and the sum of sa-cortisol and cortisone exhibited poorer diagnostic performance than sa-cortisol. The correlation between sa-cortisol and s-cortisol was best described by a model incorporating two regression lines (R2 = 0.80). Segmented regression analysis identified a breakpoint at sa-cortisol 9.7 nmol/L and s-cortisol 482 nmol/L, likely corresponding to saturation of cortisol binding globulin (CBG). Healthy subjects on oral estrogens demonstrated a linear agreement between s- and sa-cortisol through all measurements. Seventeen healthy subjects repeated the test, with similar outcome, but reproducibility in terms of intraclass coefficient and correlation was poor., Conclusions: Sa-cortisol in cosyntropin-test has high diagnostic accuracy in detecting adrenal insufficiency, and is particularly useful in women on oral estrogens. A sa-cortisol > 12.6 nmol/L assayed with LCMS/MS 60 min after 250µg cosyntropin is normal., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Aims: To describe trends in risk factor control and serious hypoglycaemia in people with type 1 diabetes and to assess the effect of starting continuous glucose monitoring (CGM) in the real-world setting., Methods: Two cross-sectional surveys including 5746 individuals in 2012 and 18,984 individuals in 2020 based on data recorded in the Norwegian Diabetes Register for Adults (NDR-A) and an analysis of a longitudinal cohort of 2057 individuals where data on CGM and HbA1c were available in the NDR-A in 2012 and 2020., Results: In the cross-sectional surveys mean HbA1c decreased from 66 mmol/mol (99% CI 65, 66) (8.2%) in 2012 to 61 mmol/mol (99% CI 61, 61) (7.7%) in 2020 (p < 0.0001). The proportion reporting serious hypoglycaemia decreased from 16.9 to 6.2% in 2020 (p < 0.0001). Mean LDL-cholesterol decreased from 2.80 (99% CI 2.78, 2.83) to 2.63 (99% CI 2.61, 2.65) mmol/l in 2020 (p < 0.0001). Mean blood pressure increased slightly. In the CGM cohort, we found a 3 mmol/mol (0.3%) greater improvement in mean HbA1c and a greater reduction in serious hypoglycaemia (-12.3% vs. -6.2%) among individuals that had started using CGM between 2013 and 2020 when compared with individuals that had not started using CGM., Conclusions: Between 2012 and 2020, we found marked improvements in glycaemic control and a considerable decrease in the proportion of individuals reporting serious hypoglycaemia. The proportion of individuals using CGM increased substantially and individuals that had started using CGM by 2020 showed greater improvement in glycaemic control and less serious hypoglycaemia., (© 2024 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Context: Graves disease (GD) is a leading cause of hyperthyroidism. Detailed investigations and predictors of long-term outcomes are missing., Objective: This work aimed to investigate the outcomes in GD 25 years after initiating antithyroid drug treatment, including disease course, clinical and biochemical predictors of relapse, and quality of life., Methods: A retrospective follow-up was conducted of GD patients that participated in a randomized trial from 1997 to 2001. Demographic and clinical data were obtained from medical records and questionnaires. Biobank samples were analyzed for inflammatory biomarkers and compared with age- and sex-matched healthy individuals., Results: We included 83% (182/218) of the patients from the original study. At the end of follow-up, normal thyroid function was achieved in 34%. The remaining had either active disease (1%), spontaneous hypothyroidism (13%), or had undergone ablative treatment with radioiodine (40%) or thyroidectomy (13%). Age younger than or equal to 40 years, thyroid eye disease (TED), smoking, and elevated levels of interleukin 6 and tumor necrosis factor receptor superfamily member 9 (TNFRS9) increased the risk of relapsing disease (odds ratio 3.22; 2.26; 2.21; 1.99; 2.36). At the end of treatment, CD40 was lower in patients who maintained normal thyroid function (P = .04). At the end of follow-up, 47% had one or more autoimmune diseases, including vitamin B12 deficiency (26%) and rheumatoid arthritis (5%). GD patients who developed hypothyroidism had reduced quality of life., Conclusion: Careful lifelong monitoring is indicated to detect recurrence, hypothyroidism, and other autoimmune diseases. Long-term ATD treatment emerges as a beneficial first-line treatment option, especially in patients with young age at onset or presence of TED., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical characteristics of alemtuzumab-induced GD., Methods: Retrospective follow-up study of MS patients treated with alemtuzumab from 2014 to 2020, including clinical course of GD, pregnancy outcome, and thyroid eye disease (TED)., Results: We enrolled 183 of 203 patients (90%, 68% women) treated with alemtuzumab at 4 hospitals in Norway. Seventy-five (41%) developed thyroid dysfunction, of whom 58 (77%) had GD. Median time from the first dose of alemtuzumab to GD diagnosis was 25 months (range, 0-64). Twenty-four of 58 GD patients (41%) had alternating phases of hyper- and hypothyroidism. Thyrotropin receptor antibodies became undetectable in 23 of 58 (40%) and they could discontinue antithyroid drug treatment after a median of 22 (range, 2-58) months. Conversely, 26 (44%) had active disease during a median follow-up of 39 months (range, 11-72). Two patients (3%) received definitive treatment with radioiodine, 6 (10%) with thyroidectomy. Nine developed TED (16%), 7 had mild and 2 moderate to severe disease. Four patients completed pregnancy, all without maternal or fetal complications. Patients who developed GD had a lower frequency of new MS relapses and MRI lesions than those without., Conclusion: GD is a very common complication of alemtuzumab treatment and is characterized by alternating hyper- and hypothyroidism. Both remission rates and the prevalence of TED were lower than those reported for conventional GD. Pregnancies were uncomplicated and GD was associated with a lower risk of subsequent MS activity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: To estimate diabetes distress prevalence and associations with demographic and clinical variables among adults with type 1 diabetes in Norway., Research Design and Methods: In this nationwide population-based registry study, the 20-item Problem Areas in Diabetes (PAID-20) questionnaire was sent to 16,255 adults with type 1 diabetes. Linear regression models examined associations of demographic and clinical variables with distress., Results: In total, 10,186 individuals (62.7%) completed the PAID-20, with a mean score of 25.4 (SD 18.4) and 21.7% reporting high distress. Respondents endorsed worrying about the future and complications as the most problematic item (23.0%). Female sex, younger age, non-European origin, primary education only, unemployment, smoking, continuous glucose monitoring use, more symptomatic hypoglycemia, reduced foot sensitivity, treated retinopathy, and higher HbA1c were associated with higher distress., Conclusions: Diabetes distress is common among adults with type 1 diabetes and associated with clinically relevant factors, underlining that regular care should include efforts to identify and address distress., (© 2023 by the American Diabetes Association.)

Purpose: Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves disease. Patients may be severely affected with eyelid retraction, exophthalmos, diplopia, pain, and threatened vision. Autoantibodies against thyroid-stimulating hormone receptor and insulin-like growth factor 1 receptor have shown associations with pathophysiological and clinical traits. Autoantibodies against thyroid-stimulating hormone receptor is in current clinical use as biomarker, but not with unambiguous diagnostic performance. A biomarker with high diagnostic accuracy and/or prognostic capability would be of immense value in diagnosing TED, especially in subclinical cases or when TED precedes the thyroid dysfunction. This article is a literature review on molecular biomarkers of TED., Methods: A literature search was performed using PubMed and Embase. Studies on molecular biomarkers in blood, tear fluid, and urine were included in the review., Results: Forty-six papers were included, of which 30, 14, and 2 studies on biomarkers in blood, tears, and urine, respectively. Fourteen of the papers evaluated the diagnostic performance of various biomarkers, 12 in blood and 2 in tears. Most studies evaluated single biomarkers, but 3 tested a panel of several markers. Except for autoantibodies against thyroid-stimulating hormone receptor, the reported diagnostic performances for the biomarkers were not confirmed in independent cohorts. In 32 studies, no or insufficient performance data were given, but the findings indicated involvement of various biologic mechanisms in TED including inflammation, oxidative stress, fibrosis, lipid metabolism, and ocular surface microflora., Conclusions: Currently, serum autoantibodies against thyroid-stimulating hormone receptor is the only molecular biomarker with clinical utility in patients with TED. Several potential biomarkers have been investigated, and particularly panels of multiple biomarkers in tears are promising. To improve patient care, biomarkers in TED should be studied further., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Objective: To map inflammatory biomarkers in patients with autonomous cortisol secretion (ACS) and overt Cushing syndrome (CS)., Method: Observational study including serum from prospectively included patients with ACS (n = 63), adrenal CS (n = 2), pituitary CS (n = 8), and healthy subjects (n = 120). Serum samples were analysed for 92 inflammatory biomarkers using proximity extension assay (OLINK)., Results: Combined, the ACS and CS patients displayed significant differences in levels of 49/92 inflammatory biomarkers (46 increased/3 decreased) compared with healthy controls. No differences in biomarker levels were found between ACS and overt CS, and none of the biomarkers correlated with the degree of hypercortisolism. Postoperative samples were available for 17 patients, median 24 months (range 6-40) after surgery and biochemical curation. There was no significant normalization of the biomarkers postoperatively., Conclusion: There was a systemic rise in inflammatory biomarkers in patients with ACS and CS, not correlated to the degree of hypercortisolism. These biomarkers were not normalized following biochemical cure., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Background: Patients with type 1 diabetes mellitus (T1DM) and poor glycaemic control are at high risk of developing microvascular and macrovascular complications. The aim of this study was to determine if a quality improvement collaborative (QIC) initiated by the Norwegian Diabetes Register for adults (NDR-A) could reduce the proportion of patients with T1DM with poor glycaemic control (defined as glycated haemoglobin (HbA1c)≥75 mmol/mol) and reduce mean HbA1c at participating clinics compared with 14 control clinics., Method: Multicentre study with controlled before and after design. Representatives of 13 diabetes outpatient clinics (n=5145 patients with T1DM) in the intervention group attended four project meetings during an 18-month QIC. They were required to identify areas requiring improvement at their clinic and make action plans. Continuous feedback on HbA1c outcomes was provided by NDR-A during the project. In total 4084 patients with type 1 diabetes attended the control clinics., Results: Between 2016 and 2019, the overall proportion of patients with T1DM and HbA1c≥75 mmol/mol in the intervention group were reduced from 19.3% to 14.1% (p<0.001). Corresponding proportions in the control group were reduced from 17.3% (2016) to 14.4% (2019) (p<0.001). Between 2016 and 2019, overall mean HbA1c decreased by 2.8 mmol/mol (p<0.001) at intervention clinics compared with 2.3 mmol/mol (p<0.001) at control clinics. After adjusting for the baseline differences in glycaemic control, there were no significant differences in the overall improvement in glycaemic control between intervention and control clinics., Conclusions: The registry linked QIC did not result in a significantly greater improvement in glycaemic control at intervention clinics compared with control clinics. However, there has been a sustained improvement in glycaemic control and importantly a significant reduction in the proportion of patients with poor glycaemic control at both intervention and control clinics during and after the QIC time frame. It is possible that some of this improvement may be due to a spillover effect from the QIC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Graves disease (GD) is one of the most common autoimmune disorders. Recent literature has shown an immune response involving several different inflammatory related proteins in these patients., Objective: This work aimed to characterize the kynurenine pathway, activated during interferon-γ (IFN-γ)-mediated inflammation and cellular (T-helper type 1 [Th1] type) immunity, in GD patients with and without thyroid eye disease (TED)., Methods: We analyzed 34 biomarkers by mass spectrometry in serum samples from 100 patients with GD (36 with TED) and 100 matched healthy controls. The analytes included 10 metabolites and 3 indices from the kynurenine pathway, 6 microbiota-derived metabolites, 10 B-vitamers, and 5 serum proteins reflecting inflammation and kidney function., Results: GD patients showed significantly elevated levels of 7 biomarkers compared with healthy controls (omega squared [ω2] > 0.06; P < .01). Of these 7, the 6 biomarkers with the strongest effect size were all components of the kynurenine pathway. Factor analysis showed that biomarkers related to cellular immunity and the Th1 responses (3-hydroxykynurenine, kynurenine, and quinolinic acid with the highest loading) were most strongly associated with GD. Further, a factor mainly reflecting acute phase response (C-reactive protein and serum amyloid A) showed weaker association with GD by factor analysis. There were no differences in biomarker levels between GD patients with and without TED., Conclusion: This study supports activation of IFN-γ inflammation and Th1 cellular immunity in GD, but also a contribution of acute-phase reactants. Our finding of no difference in systemic activation of the kynurenine pathway in GD patients with and without TED implies that the local Th1 immune response in the orbit is not reflected systemically., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Inhibitors of sodium glucose cotransporter 2 (SGLT2 inhibitors) are increasingly being used to treat type 2 diabetes. Results from previous studies suggest a rising incidence of diabetic ketoacidosis with the use of this medication., Material and Method: We performed a diagnosis search in the electronic patient records at Haukeland University Hospital for the period 1 January 2013-31 May 2021 with the aim of identifying patients with diabetic ketoacidosis who used SGLT2 inhibitors. A total of 806 patient records were reviewed., Results: Twenty-one patients were identified. Thirteen had severe ketoacidosis, and ten had normal blood glucose levels. Probable triggering causes were found in 10 of the 21, with recent surgery being the most common (n = 6). Three of the patients were not tested for ketones, and 9 were not tested for antibodies to rule out type 1 diabetes., Interpretation: The study showed that severe ketoacidosis occurs in patients with type 2 diabetes using SGLT2 inhibitors. It is important to be aware of this risk and the fact that ketoacidosis can occur without hyperglycaemia. Arterial blood gas and ketone tests must be performed to make the diagnosis.

Objective: To define liquid chromatography tandem mass spectrometry (LC-MS/MS)-based cutoff levels and panels of steroid hormones, to improve diagnosis of nonclassic congenital adrenal hyperplasia (NCCAH) and other partial enzyme defects in the adrenals., Design: Prospective cohort analysis., Setting: University hospital-based tertiary endocrine center., Patients: One hundred and twenty-one healthy adults and 65 patients evaluated for possible NCCAH (validation cohort)., Interventions: The LC-MS/MS-determined cutoffs for 11 steroids (basal and cosyntropin-stimulated) were defined by 2.5% and 97.5% percentile in healthy subjects. Validation cohort was used for comparison., Main Outcome Measures: Percentage of patients diagnosed with NCCAH among patients with polycystic ovary syndrome (PCOS)-like symptomatology. Evaluation of the defined LC-MS/MS-based cutoff levels for steroid hormones among this patient group., Results: Of the 65 PCOS-like patients evaluated for possible NCCAH, 8 (12.5%) were discovered and genetically verified, and 2 had classic congenital adrenal hyperplasia. Cosyntropin-stimulated 17-hydroxyprogesterone (17OHP) showed the best diagnostic accuracy for NCCAH with an area under the curve of 0.95 (0.89-1.0 with a sensitivity of 86% and a specificity of 88%. In homozygote patients, 21-deoxycortisol and 17OHP levels were elevated, in heterozygote patients only 17OHP (basal or stimulated) was raised. Four healthy patients in the validation cohort had 17OHP above the basal cutoff., Conclusions: The NCCAH syndrome is frequent in patients with suspected PCOS, and should be considered as a routine screening when assessing infertility. We suggest the use of serum steroid profiling, including 21-deoxycortisol, together with the cosyntropin stimulation test with 17OHP. Our data support a 17OHP cutoff of 8.5 nmol/L (2.8 ng/mL) 60 minutes after cosyntropin stimulation, when measured with LC-MS/MS, significantly lower than current European guidelines., Clinical Trials Number: NCT0218660., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To study the fear of Covid 19 infection among Norwegian patients with type 1 diabetes., Research Design and Methods: Fear of Covid 19 scale, a validated scale assessing the fear of Covid 19, was sent electronically to 16255 patients with type 1 diabetes in May 2021. The items are rated on a scale from 1 to 5 (total scores from 7 to 35). The higher the score, the greater the fear., Results: 10145 patients, 52% of the Norwegian adult type 1 diabetes population, completed the questionnaire. The mean total fear score was 13.8 (SD 5.8). Women experienced more fear than men (OR 1.96), and fear increased significantly with increasing age for both genders (p<0.05). Fear increased with increasing BMI, more pronounced for men than women. Fear was positively correlated to HbA1c (Spearman rho 0.067, p<0.05), and significantly increased in patients with micro- and macrovascular complications, compared with patients without complications (p<0.05). Smokers showed increased fear compared with non-smokers, (1.59 (1.39-1.81)), and non-European patients reported more fear than Europeans (OR of 2.02 (95% CI 1.55-2.63)., Conclusion: Assessment of fear of Covid 19 in the type 1 diabetes population in Norway revealed an overall low fear during the third wave of infection. Patients considered to be at high risk of serious disease, such as older individuals, smokers and obese individuals expressed more fear than low risk individuals. The degree of fear was also associated with sex, ethnicity, educational/working status, glycemic control and presence of complications., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The aim of this study is to identify biochemical inflammatory markers predicting the presence or risk of developing thyroid eye disease (TED) in patients with Graves' disease (GD)., Methods: Patients with GD (n = 100, 77 females) were included from the National Norwegian Registry of Organ-Specific Diseases. Serum samples were analysed for 92 different inflammatory biomarkers using the proximity extension assay. Biomarker levels were compared between groups of patients with and without TED and healthy subjects (HS) (n = 120)., Results: TED was found in 36 of 100 GD patients. Significant (P < 0.05) differences in the levels of 52 inflammatory biomarkers were found when GD patients and HS were compared (42 elevated and 10 decreased). Out of the 42 elevated biomarkers, a significantly higher serum level of interleukin-6 (IL6) (P = 0.022) and macrophage colony-stimulating factor (CSF1) (P = 0.015) were found in patients with TED compared to patients without TED. Patients with severe TED also had significantly elevated levels of Fms-related tyrosine kinase 3 ligand (FLT3LG) (P = 0.009). Furthermore, fibroblast growth factor 21 (FGF21) was significantly increased (P = 0.008) in patients with GD who had no signs of TED at baseline but developed TED later., Conclusion: We demonstrate an immunologic fingerprint of GD, as serum levels of several inflammation-related proteins were elevated, while others were decreased. Distinctly increased levels of IL6, CSF1, FLT3LG, and FGF21 were observed in TED, suggesting that these inflammatory proteins could be important in the pathogenesis, and therefore potential new biomarkers for clinical use.

Background: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined., Objective: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS., Design: Cross-sectional study., Setting: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016)., Participants: 1305 prospectively recruited persons with benign adrenal tumors., Measurements: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry., Results: Of the 1305 participants, 49.7% had NFAT ( n  = 649; 64.1% women), 34.6% had MACS-1 ( n  = 451; 67.2% women), 10.7% had MACS-2 ( n  = 140; 73.6% women), and 5.0% had CS ( n  = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased., Limitations: Cross-sectional design; possible selection bias., Conclusion: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes., Primary Funding Source: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Background: Diagnosing Cushing syndrome (CS) can be challenging. The 24-hour urine free cortisol (UFC) measurement is considered gold standard. This is a laborious test, dependent on correct urine collection. Late-night salivary cortisol is easier and is used as a screening test for CS in adults, but has not been validated for use in children., Objective: To define liquid chromatography tandem mass spectrometry (LC-MS/MS)-based cutoff values for bedtime and morning salivary cortisol and cortisone in children, and validate the results in children with and without CS., Methods: Bedtime and morning salivary samples were collected from 320 healthy children aged 4 to 16 years. Fifty-four patients from the children's outpatient obesity clinic and 3 children with pituitary CS were used for validation. Steroid hormones were assayed by LC-MS/MS. Cutoff levels for bedtime salivary cortisol and cortisone were defined by the 97.5% percentile in healthy subjects., Results: Bedtime cutoff levels for cortisol and cortisone were 2.4 and 12.0 nmol/L, respectively. Applying these cutoff levels on the verification cohort, 1 child from the obesity clinic had bedtime salivary cortisol exceeding the defined cutoff level, but normal salivary cortisone. All 3 children with pituitary CS had salivary cortisol and cortisone far above the defined bedtime cutoff levels. Healthy subjects showed a significant decrease in salivary cortisol from early morning to bedtime., Conclusions: We propose that bedtime salivary cortisol measured by LC-MS/MS with a diagnostic threshold above 2.4 nmol/L can be applied as a screening test for CS in children. Age- and gender-specific cutoff levels are not needed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Background & Aims: Obesity is associated with higher extracellular fluid (ECF) compared to intracellular fluid (ICF) volume and this dysregulation is associated with hypertension and abdominal obesity, associated with metabolic syndrome. As sodium is predominantly an extracellular cation, a higher ECF/ICF ratio will lower serum sodium concentration. The aim of the study was to see whether weight loss, due to dieting and bariatric surgery, had any impact on serum sodium concentrations in patients with severe obesity., Methods: Patients with a BMI ≥35 kg/m 2 admitted for bariatric surgery at Innlandet Hospital Trust, Norway during 2012-14 were included in the study (n = 119). Clinical data and blood samples were recorded at inclusion, after mean six months of dieting, as well as six and 12 months after bariatric surgery., Results: At inclusion, mean serum sodium was in the lower normal range, 138.3 (SD 2.4) mmol/L, but increased to 141.8 (SD 1.9) mmol/L after weight loss. The increase was significantly correlated to total weight loss (rho: 0.29, p = 0.007). Twelve months after surgery, serum sodium was significantly higher in patients with a normal BMI (<25 kg/m 2 ) compared to patients with overweight., Conclusion: Obesity and hypertension are associated with body fluid dysregulation affecting serum sodium concentrations. As mild hyponatremia, even within the normal sodium range, is associated with increased total mortality and major cardiovascular disease events, serum sodium might be a potential risk marker in patients with obesity., Competing Interests: Declaration of competing interest All authors have made a substantial contribution to research design or the acquisition, analysis, or interpretation of data and have approved the submitted and final versions:, (Copyright © 2020 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Objective: Autonomous cortisol secretion (ACS) is a condition with ACTH-independent cortisol overproduction from adrenal incidentalomas (AI) or adrenal hyperplasia. The hypercortisolism is often mild, and most patients lack typical clinical features of overt Cushing's syndrome (CS). ACS is not well defined and diagnostic tests lack validation., Methods: Retrospective study of 165 patients with AI evaluated clinically and by assay of morning plasma ACTH, late-night saliva cortisol, serum DHEA sulphate (DHEAS), 24-h urine-free cortisol, and cortisol after dexamethasone suppression., Results: Patients with AI (n = 165) were diagnosed as non-functioning incidentalomas (NFI) (n = 82) or ACS (n = 83) according to current European guidelines. Late-night saliva cortisol discriminated poorly between NFI and ACS, showing a high rate of false-positive (23/63) and false-negative (38/69) results. The conventional low-dose dexamethasone suppression test (LDDST) did not improve the diagnostic specificity, compared with the 1 mg overnight DST. Receiver operating characteristic curve analysis of DHEAS in the two cohorts demonstrated an area under the curve of 0.76 (P < 0.01) with a sensitivity for ACS of 58% and a specificity of 80% using the recommended cutoff at 1.04 µmol/L (40 µg/dL)., Conclusion: We here demonstrate in a large retrospective cohort of incidentaloma patients, that neither DHEAS, late-night saliva cortisol nor 24-h urine free cortisol are useful to discriminate between non-functioning adrenal incidentalomas and ACS. The conventional LDDST do not add further information compared with the 1 mg overnight DST. Alternative biomarkers are needed to improve the diagnostic workup of ACS.

Context: Autonomous cortisol secretion (ACS) can be unilateral or bilateral irrespective of the presence of an adrenal tumor. A reliable method to distinguish between unilateral and bilateral ACS is lacking., Objective: Evaluate the use of adrenal venous sampling (AVS) to distinguish between unilateral and bilateral ACS., Design and Methods: This was a prospective study of AVS in patients with adrenal tumors who received a diagnosis of ACS or adrenal Cushing syndrome (CS). Unilateral secretion was defined as >2.3-fold difference in cortisol levels between the two adrenal veins. Metanephrine levels were used to ascertain correct catheter position. Results were correlated with findings on CT and iodine-131-cholesterol scintigraphy., Results: Thirty-nine patients underwent AVS; there were no complications. The procedure was inconclusive in six patients and repeated with success in one, giving a success rate of 85%, and leaving 34 procedures for evaluation (adrenal CS, n = 2; ACS, n = 32). Of 14 patients with bilateral tumors, 10 had bilateral and 4 had unilateral overproduction. Of 20 patients with unilateral tumors, 11 had lateralization to the side of the tumor and the remaining had bilateral secretion. Cholesterol scintigraphy findings were concordant with those of AVS in 13 of 18 cases (72%) and discordant in 5 (28%)., Conclusion: Laterality of ACS does not always correspond to findings on CT images. AVS is a safe and valuable tool for differentiation between unilateral and bilateral cortisol secretion and should be considered when operative treatment of ACS is a possibility.

Background: The cosyntropin test is used to diagnose adrenal insufficiency (AI) and nonclassical congenital adrenal hyperplasia (NCCAH). Current cutoffs for cortisol and 17-hydroxyprogesterone (17-OHP) are derived from nonstandardized immunoassays. Liquid chromatography tandem mass spectrometry (LC-MS/MS) offers direct measurement of steroids, prompting the need to re-establish normal ranges., Objective: The goal of this study was to define cutoff values for cortisol and 17-OHP in serum by LC-MS/MS 30 and 60 minutes after intravenous administration of 250 µg tetracosactide acetate to healthy volunteers and to compare the results with LC-MS/MS with routine immunoassays., Methods: Cosyntropin testing was performed in healthy subjects (n = 138) and in patients referred for evaluation of adrenocortical function (n = 94). Steroids were assayed by LC-MS/MS and compared with two immunoassays used in routine diagnostics (Immulite and Roche platforms). The cutoff level for cortisol was defined as the 2.5% percentile in healthy subjects not using oral estrogens (n = 121) and for 17-OHP as the 97.5% percentile., Results: Cortisol cutoff levels for LC-MS/MS were 412 and 485 nmol/L at 30 and 60 minutes, respectively. Applying the new cutoffs, 13 of 60 (22%) subjects who had AI according to conventional criteria now had a normal test result. For 17-OHP, the cutoff levels were 8.9 and 9.0 nmol/L at 30 and 60 minutes, respectively., Conclusions: LC-MS/MS provides cutoff levels for cortisol and 17-OHP after cosyntropin stimulation that are lower than those based on immunoassays, possibly because cross-reactivity between steroid intermediates and cortisol is eliminated. This reduces the number of false-positive tests for AI and false-negative tests for NCCAH.

Objectives: The overnight dexamethasone (DXM) suppression test (DST) has high sensitivity, but moderate specificity, for diagnosing hypercortisolism. We have evaluated if simultaneous measurement of S-DXM may correct for variable DXM bioavailability and increase the diagnostic performance of DST, and if saliva (sa) is a feasible adjunct or alternative to serum., Design and Methods: Prospective study of DST was carried out in patients with suspected Cushing's syndrome (CS) ( n  = 49), incidentaloma ( n  = 152) and healthy controls ( n  = 101). Cortisol, cortisone and DXM were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Results: Three hundred and two subjects underwent DST; S-cortisol was ≥50 nmol/L in 83 patients, of whom 11 had CS and 27 had autonomous cortisol secretion. The lower 2.5 percentile of S-DXM in subjects with negative DST ( n  = 208) was 3.3 nmol/L, which was selected as the DXM cut-off level. Nine patients had the combination of low S-DXM and positive DST. Of these, three had been misdiagnosed as having autonomous cortisol secretion. DST results were highly reproducible and confirmed in a replication cohort ( n  = 58). Patients with overt CS had significantly elevated post-DST sa-cortisol and sa-cortisone levels compared with controls; 23 of 25 with autonomous cortisol secretion had elevated sa-cortisone and 14 had elevated sa-cortisol., Conclusions: Simultaneous measurement of serum DXM and cortisol reduced false-positive DSTs by 20% and improved the specificity. S-DXM >3.3 nmol/L is sufficient for the suppression of cortisol <50 nmol/L. Measurement of glucocorticoids in saliva is a non-invasive and easy procedure and post-DST sa-cortisone was found particularly useful in the diagnosis of CS., (© 2017 European Society of Endocrinology.)