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  • 1.
    Bäcklund, Nils
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Diagnosing hyper- and hypocortisolism using saliva samples: pitfalls and how to avoid them2023Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Background: Cushing's syndrome (CS) is caused by high cortisol secretion whereas insufficient cortisol secretion is called adrenal insufficiency (AI). Both are rare diseases with substantial diagnostic delay, and high morbidity and mortality even though effective treatment is available. This thesis aims to improve diagnostic tests for CS and AI using analyses of cortisol and its inactive metabolite cortisone in saliva samples.

    Methods: Papers 1 and 2 are based on a reference cohort including 155 individuals and 22 patients with CS. Salivary samples were collected at late-night (23:00 hours ± 15 minutes) and after a 1-mg overnight dexamethasone suppression test (DST). In Paper 1, reference intervals for salivary cortisol and cortisone analyzed with liquid chromatography-tandem mass spectrometry (LC-MS/MS) were established for late-night and post-DST samples. Diagnostic accuracy for CS was calculated using the established reference intervals. Potential effects of age, comorbidities, season, and sampling time point were also studied. In Paper 2, different analytical methods for measurement of salivary cortisol (3 LC-MS/MS and 3 immunoassays) and salivary cortisone (3 LC-MS/MS assays) were compared regarding reference intervals and diagnostic accuracies for CS. Paper 3 elucidated the potential effect of liquorice consumption, blood contamination, and topical hydrocortisone handling prior to sampling on salivary cortisol and cortisone. Paper 4 investigated whether salivary cortisol and cortisone are less affected than plasma cortisol by estrogen-containing oral contraceptive (OCs) in women undergoing a short Synacthen test (SST) by comparing the response in women with (n=41) and without OCs (n=46).

    Results: Paper 1 established reference intervals for salivary cortisol and cortisone at 23:00 hours and after DST. Using the upper reference limits as cut-offs, the diagnostic tests rendered high diagnostic accuracy for CS using salivary cortisol (sensitivity 90–95 %, specificity 96 %). There was no seasonal variation and no significant difference between samples collected at 22:00 vs 23:00 hours. Salivary cortisone showed a higher diagnostic accuracy for CS (sensitivity 100 % and specificity 94–95 %) and was less affected by other comorbidities compared to salivary cortisol. Paper 2 showed very high agreement between the three LC-MS/MS methods and that measuring salivary cortisol with immunoassays resulted in higher cortisol concentrations than with LC-MS/MS. However, using the newly established reference limits for each method, all had high diagnostic accuracy for CS. Late-night salivary cortisone analyzed with the LC-MS/MS methods and salivary cortisol analyzed with the Roche immunoassay showed the highest diagnostic accuracies. Paper 3 showed that liquorice consumption increased late-night salivary cortisol, which was sustained for up to 6 days, whereas no effect was seen on salivary cortisone. Salivary cortisol, but not cortisone, was increased by contamination of saliva with ≥0.5 % blood, which could be revealed by a clearly visible red discoloration of the saliva. Handling of topical hydrocortisone before saliva sampling affected salivary cortisol to a much higher degree than salivary cortisone. Paper 4 showed that women using OCs have considerably higher plasma cortisol levels during an SST, whereas salivary cortisol and salivary cortisone were lower compared to controls. However, the lower reference limits were not significantly different for salivary measurands, with salivary cortisone slightly more robust, opting for a common cut-off to exclude AI regardless of OCs.

    Conclusion: Using the reference intervals calculated for several clinically used analytical methods showed high diagnostic accuracy for CS, with cortisone showing the highest accuracy. Analyzing salivary cortisone was not affected by liquorice consumption or blood contamination. Salivary cortisone was least affected by OCs during an SST. In summary, salivary cortisone is very useful in the diagnostic work-up for CS and AI.

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  • 2.
    Bäcklund, Nils
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Brattsand, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Israelsson, Marlen
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ragnarsson, Oskar
    Burman, Pia
    Edén Engström, Britt
    Høybye, Charlotte
    Berinder, Katarina
    Wahlberg, Jeanette
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Dahlqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Reference intervals of salivary cortisol and cortisone and their diagnostic accuracy in Cushing's syndrome2020In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 182, no 6, p. 569-582Article in journal (Refereed)
    Abstract [en]

    Objective: The challenge of diagnosing Cushing's syndrome (CS) calls for high precision biochemical screening. This study aimed to establish robust reference intervals for, and compare the diagnostic accuracy of, salivary cortisol and cortisone in late-night samples and after a low-dose (1 mg) dexamethasone suppression test (DST).

    Design and methods: Saliva samples were collected at 08:00 and 23:00 h, and at 08:00 h, after a DST, from 22 patients with CS and from 155 adult reference subjects. We also collected samples at 20:00 and 22:00 h from 78 of the reference subjects. Salivary cortisol and cortisone were analysed with liquid chromatography-tandem mass spectrometry. The reference intervals were calculated as the 2.5th and 97.5th percentiles of the reference population measurements. Diagnostic accuracies of different tests were compared, based on areas under the receiver-operating characteristic curves.

    Results: The upper reference limits of salivary cortisol and cortisone at 23:00 h were 3.6 nmol/L and 13.5 nmol/L, respectively. Using these reference limits, CS was detected with a sensitivity (95% CI) of 90% (70-99%) and specificity of 96% (91-98%) for cortisol, and a 100% (84-100%) sensitivity and 95% (90-98%) specificity for cortisone. After DST, cortisol and cortisone upper reference limits were 0.79 nmol/L and 3.5 nmol/L, respectively. CS was detected with 95% (75-100%) sensitivity and 96% (92-99%) specificity with cortisol, and 100% (83-100%) sensitivity and 94% (89-97%) specificity with cortisone. No differences in salivary cortisol or cortisone levels were found between samples collected at 22:00 and 23:00 h.

    Conclusion: Salivary cortisol and cortisone in late-night samples and after DST showed high accuracy for diagnosing CS, salivary cortisone being slightly, but significantly better.

  • 3.
    Bäcklund, Nils
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Brattsand, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Lundstedt, Staffan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Aardal, Elisabeth
    Department of Clinical Chemistry, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Bartuseviciene, Inga
    Department of Clinical Chemistry, Karolinska University Hospital, Stockholm, Sweden.
    Berinder, Katarina
    Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden.
    Höybye, Charlotte
    Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden; Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden.
    Burman, Pia
    Department of Endocrinology, Skåne University Hospital, Malmö, Sweden.
    Edén Engström, Britt
    Department of Medical Sciences, Endocrinology and Mineral Metabolism, Uppsala University, Uppsala, Sweden; Department of Endocrinology and Diabetes, Uppsala University Hospital, Uppsala, Sweden.
    Isaksson, Anders
    Department of Clinical Chemistry and Pharmacology, Lund University, Lund, Sweden.
    Blomgren, Anders
    Department of Clinical Chemistry and Pharmacology, Lund University, Lund, Sweden.
    Ragnarsson, Oskar
    Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden; Department of Endocrinology, Sahlgrenska University Hospital, Göteborg, Sweden.
    Rüetschi, Ulrika
    Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Wahlberg, Jeanette
    School of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Dahlqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Salivary cortisol and cortisone in diagnosis of Cushing's syndrome: a comparison of six different analytical methods2023In: Clinical Chemistry and Laboratory Medicine, ISSN 1434-6621, E-ISSN 1437-4331, Vol. 61, no 10, p. 1780-1791Article in journal (Refereed)
    Abstract [en]

    Objectives: Salivary cortisol and cortisone at late night and after dexamethasone suppression test (DST) are increasingly used for screening of Cushing’s syndrome (CS). We aimed to establish reference intervals for salivary cortisol and cortisone with three liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques and for salivary cortisol with three immunoassays (IAs), and evaluate their diagnostic accuracy for CS.

    Methods: Salivary samples at 08:00 h, 23:00 h and 08:00 h after a 1-mg DST were collected from a reference population (n=155) and patients with CS (n=22). Sample aliquots were analyzed by three LC-MS/MS and three IA methods. After establishing reference intervals, the upper reference limit (URL) for each method was used to calculate sensitivity and specificity for CS. Diagnostic accuracy was evaluated by comparing ROC curves.

    Results: URLs for salivary cortisol at 23:00 h were similar for the LC-MS/MS methods (3.4–3.9 nmol/L), but varied between IAs: Roche (5.8 nmol/L), Salimetrics (4.3 nmol/L), Cisbio (21.6 nmol/L). Corresponding URLs after DST were 0.7–1.0, and 2.4, 4.0 and 5.4 nmol/L, respectively. Salivary cortisone URLs were 13.5–16.6 nmol/L at 23:00 h and 3.0–3.5 nmol/L at 08:00 h after DST. All methods had ROC AUCs ≥0.96.

    Conclusions: We present robust reference intervals for salivary cortisol and cortisone at 08:00 h, 23:00 h and 08:00 h after DST for several clinically used methods. The similarities between LC-MS/MS methods allows for direct comparison of absolute values. Diagnostic accuracy for CS was high for all salivary cortisol and cortisone LC-MS/MS methods and salivary cortisol IAs evaluated.

    The full text will be freely available from 2024-09-26 07:00
  • 4.
    Bäcklund, Nils
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Lundstedt, Staffan
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Tornevi, Andreas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Sustainable Health.
    Wihlbäck, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.
    Dahlqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Brattsand, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Comparison of plasma cortisol-, salivary cortisol- and salivary cortisone-response to the short Synacthen test in women using oral contraceptivesManuscript (preprint) (Other academic)
  • 5.
    Bäcklund, Nils
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lundstedt, Staffan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Tornevi, Andreas
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Wihlbäck, Anna-Carin
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Dahlqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Brattsand, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Salivary cortisol and cortisone can circumvent confounding effects of oral contraceptives in the short synacthen test2024In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 109, no 7, p. 1899-1906Article in journal (Refereed)
    Abstract [en]

    Context: Adrenal insufficiency (AI) is usually diagnosed by low plasma cortisol levels following a short Synacthen test (SST). Most plasma cortisol is bound to corticosteroid-binding globulin, which is increased by estrogen in combined estrogen-progestin oral contraceptives (COCs). Women with AI using COCs are therefore at risk of having an apparently normal plasma cortisol level during SST, which would not adequately reflect AI.

    Objective: To test whether salivary cortisol or cortisone during SST is more robust against the COC effect and to calculate the lower reference limits (LRLs) for these to be used as tentative diagnostic cutoffs to exclude AI.

    Methods: Forty-one healthy women on COCs and 46 healthy women without exogenous estrogens performed an SST with collection of plasma and salivary samples at 0, 30, and 60 min after Synacthen injection. The groups were compared using regression analysis with age as covariate and the LRLs were calculated parametrically.

    Results: SST-stimulated plasma cortisol levels were significantly higher in the COC group versus controls, while mean salivary cortisol and cortisone levels were slightly lower in the COC group. Importantly, COC use did not significantly alter LRLs for salivary cortisol or cortisone. The smallest LRL difference between groups was seen for salivary cortisone.

    Conclusion: Salivary cortisol and especially salivary cortisone are considerably less affected by COC use than plasma cortisol during SST. Due to similar LRLs, a common cutoff for salivary cortisol and cortisone during SST can be used to exclude AI in premenopausal women irrespective of COC use.

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  • 6.
    Imamovic, Marcus
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Bäcklund, Nils
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lundstedt, Staffan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brattsand, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Aardal, Elisabeth
    Department of Clinical Chemistry and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Dahlqvist, Per
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Confounding effects of liquorice, hydrocortisone, and blood contamination on salivary cortisol but not cortisone2023In: Endocrine Connections, E-ISSN 2049-3614, Vol. 12, no 1, article id e220324Article in journal (Refereed)
    Abstract [en]

    Objective: To determine the effects of liquorice consumption, topical hydrocortisone, and blood contamination on salivary cortisol and cortisone concentrations.

    Design and methods: Thirty healthy volunteers were randomized to a low, medium, or high dose of liquorice. Late-night saliva samples were collected using a Salivette® collection device at baseline, during 1 week of daily liquorice consumption, and during 4 weeks' washout. Saliva sampling was also performed before and after the application of topical hydrocortisone on the skin. Furthermore, in a subgroup (n  = 16), saliva and venous blood were collected from each individual and mixed to achieve graded blood contamination in saliva. Salivary cortisol and cortisone were analyzed with liquid chromatography-tandem mass spectrometry.

    Results: Significant increases in salivary cortisol concentrations were observed during medium- (+49%) and high-dose (+97%) liquorice intake, which returned to baseline 4 days after liquorice withdrawal. Topical hydrocortisone on fingers holding the collection swab increased salivary cortisol concentrations >1000-fold with concomitant pronounced elevation of the cortisol:cortisone ratio. Salivary cortisol increased significantly after contamination with blood ≥0.5%. Visual examination could safely detect these samples. Salivary cortisone concentrations were unaffected by liquorice consumption and blood contamination, and only marginally affected by topical hydrocortisone.

    Conclusion: Liquorice, topical hydrocortisone, and blood contamination may all cause elevated salivary cortisol concentrations. Improved sampling instructions and visual examination of the sample may minimize these risks. Salivary cortisone is essentially unaffected by the different preanalytical confounders and may be used as a first-line screening test for Cushing's syndrome.

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