Åse Bjorvatn Sævik

• Stokland, Ann-Elin Meling; Breivik, Lars; Dalen, Ingvild; Steintorsdottir, Sandra Dis; Kildal, Simon & Nermoen, Ingrid [Vis alle 30 forfattere av denne artikkelen] (2026). Risk and outcomes of adrenal crisis in primary adrenal insufficiency: Evidence from a 24‐year nationwide cohort study. Journal of Internal Medicine. ISSN 0954-6820. doi: 10.1111/joim.70153. Fulltekst i vitenarkiv Vis sammendrag

  Background: Adrenal crisis is a life‐threatening emergency. Despite preventive strategies, previous reports suggest increasing incidence and substantial mortality, but robust validated data are limited. Objective: To assess temporal trends in adrenal crisis incidence and identify associated risk factors. Methods: We studied 1040 patients with autoimmune or idiopathic primary adrenal insufficiency enrolled in the Norwegian Addison Registry. Medical records were reviewed for crisis‐related hospitalizations between 2000 and 2023. Overt adrenal crisis was defined by acute clinical deterioration with hemodynamic or biochemical abnormalities, whereas incipient crisis was defined by typical symptoms without objective abnormalities. Results: During a median follow‐up of 15 years, 660 patients (63%) experienced crisis‐related hospitalizations, and 265 (25%) had an overt adrenal crisis after diagnosis. The incidence of overt crises was 3.2 per 100 person‐years and that of incipient crises was 6.9 per 100 person‐years. Admission rates for incipient crises increased significantly over time ( p  < 0.001), whereas overt crisis rates remained stable. Among 1754 admissions, five deaths (0.3%) were attributed to adrenal crisis. Both younger and older age ( p  < 0.001) and type 1 diabetes (incidence rate ratio 2.09, 95% confidence interval 1.45–3.01; p  < 0.001) were associated with increased overt crisis risk. Daily corticosteroid dose was not associated with crisis risk. Prehospital stress dosing was used in about 50% of admissions. Conclusions: Overt adrenal crisis was uncommon and crisis‐related in‐hospital mortality was exceptionally low. Crisis risk was independent of replacement dose but increased in patients with type 1 diabetes. Strengthening education and implementation of prehospital stress dosing may further reduce the burden of adrenal crises.

• Sævik, Åse Bjorvatn; Ueland, Grethe Åstrøm; Åkerman, Anna-Karin; Methlie, Paal; Quinkler, Marcus & Jørgensen, Anders Palmstrøm [Vis alle 26 forfattere av denne artikkelen] (2023). Altered biomarkers for cardiovascular disease and inflammation in autoimmune Addison's disease - a cross-sectional study. European Journal of Endocrinology (EJE). ISSN 0804-4643. 189(4), s. 438–447. doi: 10.1093/ejendo/lvad136. Fulltekst i vitenarkiv Vis sammendrag

  Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood. Design Cross-sectional study. Methods We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH. Results Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = −0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (−0.15 normalized protein expression [NPX], P = .0001, and −0.25 NPX, P = .0003, respectively). Conclusions We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small.

• Åkerman, Anna-Karin; Sævik, Åse Bjorvatn; Thorsby, Per Medbøe; Methlie, Paal; Quinkler, Marcus & Jørgensen, Anders Palmstrøm [Vis alle 26 forfattere av denne artikkelen] (2023). Plasma-Metanephrines in Patients with Autoimmune Addison’s Disease with and without Residual Adrenocortical Function. Journal of Clinical Medicine. 12:3602(10), s. 1–10. doi: 10.3390/jcm12103602. Fulltekst i vitenarkiv Vis sammendrag

  Purpose: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison's disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin. Methods: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS). Results: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min (p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points (p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges. Conclusion: Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD.

• Ueland, Grethe Åstrøm; Methlie, Paal; Heie, Anette; Stokland, Ann-Elin Meling; Dahle, Anne Lise & Sævik, Åse Bjorvatn [Vis alle 8 forfattere av denne artikkelen] (2023). Substantial changes in inflammatory and cardiovascular biomarkers in patients with autonomous cortisol secretion. European Journal of Endocrinology (EJE). ISSN 0804-4643. 189(1), s. 78–86. doi: 10.1093/ejendo/lvad076. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Didriksen, Nora Møller; Sævik, Åse Bjorvatn; Sortland, Linn Solveig; Øksnes, Marianne & Husebye, Eystein Sverre (2021). Sex-Specific Limitations in Physical Health in Primary Adrenal Insufficiency. Frontiers in Endocrinology. 12. doi: 10.3389/fendo.2021.718660. Fulltekst i vitenarkiv Vis sammendrag

  Background: Patients with primary adrenal insufficiency (PAI) suffer reduced quality of life (QoL), but comparisons with large-scale normative data are scarce. The clinical characteristics associated with reduced QoL are largely unknown. Methods: Cross-sectional data on clinical characteristics and QoL scores from 494 patients were included. QoL was measured using RAND-36 (generic) and AddiQoL (-30 and -8, disease-specific). RAND-36 is reported as subdomain scores as well as physical (PCS) and metal (MCS) summary scores and compared with normative data. Results: Perception of physical role was consistently decreased across age groups in patients with PAI compared with normative data [75 (0-100) vs. 100 (50-100), p<0.001]. Men with PAI reported significantly lower scores for social functioning [88 (75-100) vs. 100 (75-100), p<0.001], as well as for vitality and physical role. In women, the greatest impairment was seen in physical role [50 (0-100) vs. 100 (50-100), p<0.001], followed by social functioning, vitality, physical function, general health, mental health, and emotional role. Overall, better QoL was associated with male sex (AddiQoL-30: 89 ± 13 vs. 82 ± 13, p<0.002), younger age (e.g. 20-29 vs. 80-89 years: PCS 59 [50-62] vs. 46 [37-53], p<0.001), autoimmune etiology [PCS: 53 (45-59) vs.. 45 (38-54), p<0.001], and absence of autoimmune comorbidity [PCS: 54 (45-59) vs. 50 (43-58), p<0.001]. There were no significant differences in QoL scores between different doses or dosing regimens of glucocorticoid or mineralocorticoid replacement. Conclusion: QoL is reduced in patients with PAI, especially perception of physical role in women and social functioning in men. Among patients with PAI, female sex, higher age, non-autoimmune etiology, and autoimmune comorbidity was associated with lower QoL-scores.

• Sævik, Åse Bjorvatn; Wolff, Anette Susanne Bøe; Björnsdottir, Sigridur; Simunkova, Katerina; Hynne, Martha Schei & Dolan, David William Peter [Vis alle 16 forfattere av denne artikkelen] (2021). Potential Transcriptional Biomarkers to Guide Glucocorticoid Replacement in Autoimmune Addison's Disease. Journal of the Endocrine Society (JES). 5(3), s. 1–10. doi: 10.1210/jendso/bvaa202. Fulltekst i vitenarkiv Vis sammendrag

  Background No reliable biomarkers exist to guide glucocorticoid (GC) replacement treatment in autoimmune Addison’s disease (AAD), leading to overtreatment with alarming and persistent side effects or undertreatment, which could be fatal. Objective To explore changes in gene expression following different GC replacement doses as a means of identifying candidate transcriptional biomarkers to guide GC replacement in AAD. Methods Step 1: Global microarray expression analysis on RNA from whole blood before and after intravenous infusion of 100 mg hydrocortisone (HC) in 10 patients with AAD. In 3 of the most highly upregulated genes, we performed real-time PCR (rt-PCR) to compare gene expression levels before and 3, 4, and 6 hours after the HC infusion. Step 2: Rt-PCR to compare expression levels of 93 GC-regulated genes in normal versus very low morning cortisol levels in 27 patients with AAD. Results Step 1: Two hours after infusion of 100 mg HC, there was a marked increase in FKBP5, MMP9, and DSIPI expression levels. MMP9 and DSIPI expression levels correlated with serum cortisol. Step 2: Expression levels of CEBPB, DDIT4, FKBP5, DSIPI, and VDR were increased and levels of ADARB1, ARIDB5, and POU2F1 decreased in normal versus very low morning cortisol. Normal serum cortisol levels positively correlated with DSIPI, DDIT4, and FKBP5 expression. Conclusions We introduce gene expression as a novel approach to guide GC replacement in AAD. We suggest that gene expression of DSIPI, DDIT4, and FKBP5 are particularly promising candidate biomarkers of GC replacement, followed by MMP9, CEBPB, VDR, ADARB1, ARID5B, and POU2F1.

• Bothou, Christina; Anand, Gurpreet; Li, Dingfeng; Kienitz, Tina; Seejore, Khyatisha & Simeoli, Chiara [Vis alle 34 forfattere av denne artikkelen] (2020). Current Management and Outcome of Pregnancies in Women with Adrenal Insufficiency: Experience from a Multicenter Survey. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 105(8), s. E2853–E2863. doi: 10.1210/clinem/dgaa266. Fulltekst i vitenarkiv
• Sævik, Åse Bjorvatn; Åkerman, Anna-Karin; Methlie, Paal; Quinkler, Marcus; Jørgensen, Anders Palmstrøm & Høybye, Charlotte [Vis alle 26 forfattere av denne artikkelen] (2020). Residual Corticosteroid Production in Autoimmune Addison Disease. Journal of Clinical Endocrinology and Metabolism (JCEM). ISSN 0021-972X. 105(7), s. 2430–2441. doi: 10.1210/clinem/dgaa256. Fulltekst i vitenarkiv Vis sammendrag

  Design: Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography–tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test. Results: Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P < 0.002) and in shorter disease duration (median 6 [0-44] vs 13 [0-53] years; P < 0.001). Residual MC production was found in 26 (13.5%) patients and associated with shorter disease duration (median 5.5 [0.5-26.0] vs 13 [0-53] years; P < 0.004), lower fludrocortisone replacement dosage (median 0.075 [0.050-0.120] vs 0.100 [0.028-0.300] mg; P < 0.005), and higher plasma renin concentration (median 179 [22-915] vs 47.5 [0.6-658.0] mU/L; P < 0.001). There was no significant association between residual production and frequency of adrenal crises or quality of life. None had a normal cosyntropin response, but peak cortisol strongly correlated with unstimulated cortisol (r = 0.989; P < 0.001) and plasma adrenocorticotropic hormone (ACTH; r = –0.487; P < 0.001). Conclusion: In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life. (J Clin Endocrinol Metab 105: 1–12, 2020) Key words: Adrenal failure; adrenal steroids; Autoimmune Addison disease; cortisol; primary adrenal insufficiency; residual function

• Sævik, Åse Bjorvatn; Åkerman, Anna Karin; Grønning, Kaja; Nermoen, Ingrid; Valland, Susanna Fonneland & Finnes, Trine Elisabeth [Vis alle 22 forfattere av denne artikkelen] (2017). Clues for early detection of autoimmune Addison's disease - myths and realities. Journal of Internal Medicine. ISSN 0954-6820. 283(2), s. 190–199. doi: 10.1111/joim.12699. Fulltekst i vitenarkiv Vis sammendrag

  BACKGROUND: Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce. OBJECTIVE: Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD. MATERIAL AND METHODS: A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values. RESULTS: Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L(-1) [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L(-1) [2-442]) than in those without (81 nmol L(-1) [1-668], P < 0.001). CONCLUSION: The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis.

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