Grethe Åstrøm Ueland

Aims: To describe trends in diabetic ketoacidosis admissions and examine factors associated with repeated admissions and mortality among adults living with type 1 diabetes. Materials and methods: Diabetic ketoacidosis admissions among adults at a Norwegian university hospital between 1 August 2012 and 31 August 2022 were retrospectively reviewed using electronic medical records. Results: A total of 178 participants with 306 admissions were included. Median [IQR] age at admission was 34 years [22–51]. Median HbA1c was 88 mmol/mol [72–105]. Diabetic ketoacidosis admission frequency decreased by an estimated 6.9% annually (RR 0.931; 95% CI 0.896–0.968; p < 0.001) over the 10-year period. 40 participants (22.5%) had more than one admission during the study period. Psychiatric illness (aOR 2.827; 95% CI 1.070–7.468; p = 0.036) and receipt of disability benefits (aOR 4.941; 95% CI 1.576–15.490; p = 0.006) were associated with experiencing more than one lifetime admission. Prior diabetic ketoacidosis, suspected treatment non-adherence and psychiatric illness were associated with higher readmission rates during follow-up. In-hospital mortality was 1.6%, and 5-year cumulative mortality was 14.7%. Alcohol or substance misuse (HR 2.499; 95% CI: 1.191–5.245; p = 0.015) and higher age at the index admission (HR 1.874; 95% CI: 1.511–2.324; p < 0.001, per 10 years) were associated with mortality in the follow-up period. Conclusions: Diabetic ketoacidosis admissions declined substantially over the 10-year study period despite growth in the hospital catchment area population, suggesting that diabetes care has improved. Repeated admissions were common and associated with psychosocial vulnerability. In-hospital mortality was low, but five-year mortality was considerable, supporting targeted follow-up after an episode of diabetic ketoacidosis.

Primary aldosteronism affects 5 to 20% of the hypertensive population and is associated with increased cardiovascular and metabolic risk compared with primary hypertension. Alterations in the dynamics of aldosterone secretion are key, but these are not well captured by current diagnostic pathways, and the disease is often missed. In this proof-of-concept study, we used ambulatory microdialysis sampling to continuously monitor tissue corticosteroid dynamics in primary aldosteronism over 24 hours. In a cohort of 60 patients, we found pulsatile nocturnal hypersecretion of aldosterone and the hybrid steroids 18-hydroxycortisol and 18-oxocortisol with a preserved daily rhythm. This was most prominent in unilateral disease, with normalization after adrenalectomy. Our findings confirm that a key pathophysiological feature of primary aldosteronism is disruption of corticosteroid rhythms rather than persistent elevation of hormones. We show that ambulatory dynamic hormone profiling is a viable technique that offers substantially more information than current diagnostic approaches relying on single–time point hormone measurements. In the future, this offers the opportunity to investigate more subtle dynamic phenotypes and potentially earlier detection of disease.

Background: Type 1 diabetes (T1D) and type 2 diabetes (T2D) differ in health care needs, and precise prevalence estimates by diabetes type are important for health care planning. Data and Methods: Using Norwegian health registry data on diagnoses from primary and specialist care and prescribed drugs, we developed a classification method to define T1D and T2D. The Norwegian Diabetes Register for Adults (NDR-A) served as reference standard. Results: First, for individuals in the NDR-A, we established a health registry data classification method with three key steps: (A) classifying T1D based on the use of insulin and diagnoses from specialist healthcare, (B) classifying T2D based on diagnoses from both specialist and primary healthcare, and (C) identifying individuals as having T1D if they were diagnosed in primary healthcare and used insulin, but never had a T2D diagnosis. Overall correspondence between NDR-A diagnosis and the classification method was 94.7% for T1D and 97.9% for T2D. For T1D, the correspondence was 97% or higher in age-groups 18-39 and 40-59, 87.6% for those aged 60-79 and 69.4% for individuals older than 80 years. For T2D, the correspondence was 97% or higher for age-groups 40 and above, and 92.1% for those aged 18-39. Applying the classification method to total population data showed that, in 2022, among 4,315,563 individuals aged 18 years and older living in Norway, 31,264 were identified as having T1D (0.72%) and 239,120 were identified as havingT2D (5.5%). Conclusion: While classifying diabetes types can be challenging, our registry-based classification corresponded well with the NDR-A.

Objective: Evaluate the impact of adrenalectomy on metabolic parameters and quality of life (QoL) in patients with mild autonomous cortisol secretion (MACS). Method: A multicenter prospective randomized clinical trial compared adrenalectomy with conservative management. Metabolic parameters and QoL were assessed at baseline and after 2 years. Results: Forty-three MACS patients with a single adrenal adenoma were randomized to either adrenalectomy (n = 21) or conservative management (n = 22). At baseline, 33 patients had hypertension, 13 had type 2 diabetes (T2D), 18 used statins, and nine patients had osteoporosis. After 2 years, normalization of cortisol levels post 1 mg dexamethasone suppression test was achieved in 19/21 adrenalectomy patients compared to 2/22 patients in the conservative group (P < 0.01). All adrenalectomy patients had a significant increase in ACTH and DHEA-S. Office blood pressure and daily defined doses of antihypertensives (DDD) improved in nine of 12 adrenalectomy patients versus four of 15 conservatively treated patients (P = 0.01). Using 24 h blood pressure and DDD, improvement rates were five of 11 in the adrenalectomy group and six of 15 in the conservative group (P = 0.78). Among patients without T2D, the 120 min glucose level during oral glucose tolerance test was lower in the adrenalectomy group (6.2 vs 7.3 mmol/L, P = 0.04), but within-group changes were not different (P = 0.76). There were no statistically significant differences in QoL between the two groups. Conclusion: Adrenalectomy showed trends toward improvement in office blood pressure and glucose metabolism in MACS, suggesting possible reduction in cardiovascular risk and metabolic complications. Clinical trials number: NCT01246739

Aims: The aim of this study is to determine the prevalence of impaired awareness of hypoglycaemia (IAH) and examine risk factors for IAH in adults with type 1 diabetes.Methods: We conducted a population‐based registry study of 10,202 adults (≥18 years) with type 1 diabetes using data from the Norwegian Diabetes Register for Adults. The registry used the 1‐item Gold scale, measuring hypoglycaemia symptom awareness. We calculated the overall prevalence of IAH (Gold score ≥4) (95% CI) and prevalence for subgroups based on demographic and clinical variables. We estimated IAH prevalence based on continuous scales of age, diabetes duration and HbA_1c using predicted probabilities from generalised additive logistic regression models. Finally, we quantified the associations of selected variables on IAH prevalence using log‐binomial regression models.Results: Overall, 18.0% reported IAH (95% CI 17.2, 18.7). The prevalence increased linearly with the participants' age, whereas the associations of diabetes duration and HbA_1c with IAH were non‐linear with higher prevalence in both lower and higher tails of their distributions. Multiple severe hypoglycaemic events, female sex, age ≥ 65 years, diabetes duration ≤4 years or ≥ 30 years, multiple DKA events and CGM use were associated with higher risk for IAH. HbA_1c 65–74 mmol/mol (8.1–8.9%) was associated with lower risk for IAH.Conclusions: In this nationwide study, the IAH prevalence was 18.0%. Multiple hypoglycaemic events, female sex and diabetes duration were identified as important risk factors for IAH. Study findings highlight the complexity of self‐reported hypoglycaemia symptom awareness and emphasise the importance of routinely addressing symptom awareness in diabetes follow‐up.

Objective: To investigate the gender differences and the disparities between infected and noninfected patients with type 2 diabetes (T2D) regarding patient‐reported experiences during the COVID‐19 pandemic in Norway.Method: Register study using questionnaires sent electronically to patients with T2D, June 2022. The questionnaire included 82 questions covering COVID‐19 disease, symptoms, medications, comorbidities, hospital care, possibility of working from home and information received from health authorities. Clinical and demographic data were collected from the Norwegian diabetes registry for adults.Results: A total of 29,079 T2D patients participated, of whom 38.1% were women. Patients infected with COVID‐19 were younger, had shorter diabetes duration and less comorbidities than noninfected (p < 0.01). Women reported significantly more anxiety, depression and fear of not getting their diabetes medication than men did. Most patients were vaccinated against COVID‐19 (98.3%), whereas approximately 60% had received seasonal flu vaccine, and only 27.2% the pneumococcal vaccine. Women described more vaccine adverse effects and long Covid symptoms. Overall, 14% experienced vaccine complications and 27.3% of infected individuals reported long Covid symptoms. 2.4% of the infected patients needed hospital admission. Patients were satisfied with the follow‐up of their diabetes, and with information from the government during the pandemic.Conclusion: Female patients were more likely to experience a prolonged Covid course, and higher degree of adverse effects from the COVID‐19 vaccine than male patients. Also, long Covid symptoms were significantly more often reported among female patients, while men were more prone to be hospitalised when infected. Hospitalised patients, both men and women, had significantly higher HbA1C than those who were not hospitalised. T2D patients had a surprisingly low pneumococcal vaccination coverage, despite recommendations in national guidelines.

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 2.5^th 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.

Objective: 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.

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.