Prevalence and Incidence of Fractures in Patients With Nonfunctional Adrenal Tumors.

Importance: It is unclear whether nonfunctional adrenal tumors (NFATs) are associated with fractures. Objective: To analyze fracture frequencies in individuals with NFATs. Design, Setting, and Participants: A national retrospective cohort study was conducted in patients with NFATs diagnosed in Sweden between January 1, 2005, and December 31, 2019, and control participants without adrenal tumors followed up until death or the end of 2019. Individuals with a diagnosis of adrenal hormonal excess or previous malignant tumors were excluded. Sensitivity analyses were performed in subgroups of individuals with a combination of gallbladder, biliary tract, and pancreas diseases (for whom it was assumed that controls would also have undergone computed tomography) and 3- and 12-month survival free of malignant tumors after the NFAT diagnosis. The data were analyzed from September to November 2023. Exposures: Diagnosis of NFATs. Main Outcomes and Measures: Main study outcomes were prevalence and incidence of fractures after adjustment for sex, age, and comorbidities. Secondary outcomes were fragility fractures, fractures with fall on the same level, and fracture locations (distal arm and vertebral and hip fractures). Fracture incidence after adrenalectomy was also studied. Results: Among 20 390 patients, 12 120 (59.4%) were women, and the median (IQR) age was 66 (57-73) years; among 125 392 controls, 69 994 (55.8%) were women, and the median (IQR) age was 66 (57-73) years. Previous fractures were more common in patients diagnosed with NFATs compared with controls (4310 of 20 390 [21.1%] vs 20 323 of 125 392 [16.2%]; odds ratio [OR], 1.39; 95% CI, 1.34-1.45; adjusted OR [AOR], 1.27; 95% CI, 1.23-1.33). During the follow-up period (median [IQR], 4.9 [2.2-8.2] years), incident fractures were more common in patients with NFATs (3127 of 20 390 [15.3%] vs 16 086 of 125 392 [12.8%]; hazard ratio [HR], 1.40; 95% CI, 1.34-1.45; adjusted HR [AHR], 1.27; 95% CI, 1.22-1.33). An association between NFATs and vertebral fractures was found (AOR, 1.51; 95% CI, 1.33-1.72; AHR, 1.83; 95% CI, 1.60-2.09). In men younger than 50 years, NFATs were associated with fractures (AOR, 1.45; 95% CI, 1.21-1.74; AHR, 1.48; 95% CI, 1.20-1.82). There was no association among individuals who had undergone adrenalectomy (AHR, 1.12; 95% CI, 0.90-1.38). The association between NFATs and fractures remained significant and of similar magnitude in all sensitivity analyses. Conclusions and Relevance: In this cohort study, NFATs were associated with fractures, particularly among younger men; thus, patients with NFATs should have bone health evaluation with appropriate treatment and monitoring, especially in younger men.

Establishment and representativeness of the Stockholm Sodium Cohort: A laboratorial and pharmacoepidemiologic database covering 1.6 million individuals in the Stockholm County.

OBJECTIVE: Hyponatremia is associated with considerable morbidity and mortality, but causal links have been difficult to establish. Here, we describe the establishment and representativeness of the Stockholm Sodium Cohort (SSC), designed to study etiologies and outcomes of hyponatremia. STUDY DESIGN AND SETTING: All residents of Stockholm County undertaking at least one serum sodium test between 2005-2018 were included in the SSC. Individual-level test results from over 100 laboratory parameters relevant to hyponatremia were collected and linked to data on demographics, socioeconomic status, healthcare contacts, diagnoses and dispensed prescription medications using national registers. RESULTS: A total of 1,632,249 individuals, corresponding to 64% of the population of Stockholm County, were included in the SSC. Coverage increased with advancing age, ranging from 32% in children and adolescents (≤18 years) to 97% among the oldest (≥80 years). The coverage of SSC included the vast majority of patients in Stockholm County diagnosed with diabetes mellitus (93%), myocardial infarction (98%), ischemic stroke (97%), cancer (85%), pneumonias requiring inpatient care (95%) and deaths (88%). CONCLUSION: SSC is the first cohort specifically designed to investigate sodium levels in a large, population-based setting. It includes a wide range of administrative health data and laboratory analyses. The coverage is high, particularly among elderly and individuals with comorbidities. Consequently, the cohort has a large potential for exploration of various aspects of hyponatremia.

Mortality in Patients With Nonfunctional Adrenal Tumors.

Importance: It is unclear if nonfunctional adrenal adenomas (NFAAs) are associated with increased mortality. Objective: To analyze mortality and causes of death in patients with NFAA. Design, Setting, and Participants: A national retrospective register-based case-control study was conducted and included 17 726 patients with a diagnosis of adrenal adenoma in Sweden from 2005 to 2019 who were identified and followed up until death or 2020 as well as 124 366 controls without adrenal adenoma. Individuals with diagnoses indicating adrenal hormonal excess or cancer were excluded. Follow-up started after 3 months of cancer-free survival following the date of the NFAA diagnosis. Sensitivity analyses were performed in subgroups of individuals for whom it was assumed that controls would also have undergone computed tomography: those with acute appendicitis (for whom it was assumed that there was no concern of cancer) and in patients with a combination of gallbladder, biliary tract, and pancreas disorders and 6-month and 12-month cancer-free survival following the date of the NFAA diagnosis. The data were analyzed in 2022. Exposures: Diagnosis of NFAA. Main Outcomes and Measures: The primary outcome was all-cause mortality among patients with NFAA after adjustment for comorbidities and socioeconomic factors. Secondary outcomes were mortality due to cardiovascular diseases and cancer. Results: Among 17 726 cases, 10 777 (60.8%) were women, and the median (IQR) age was 65 (57-73) years; among 124 366 controls, 69 514 (55.9%) were women, and the median (IQR) age was 66 (58-73) years. Among cases, overall mortality during the follow-up period (median, 6.2 years [IQR, 3.3-9.6 years]) was higher compared with controls (hazard ratio [HR] 1.43; 95 CI, 1.38-1.48; adjusted HR [aHR], 1.21; 95% CI, 1.16-1.26). The relative association of NFAA with overall mortality was similar in women and men (aHR, 1.22 [95% CI, 1.15-1.28] vs 1.19 [95% CI, 1.11-1.26]; P < .001 in both groups). In contrast, NFAA was associated with a larger increase in mortality among individuals younger than 65 years (aHR, 1.44; 95% CI, 1.31-1.58) than in older individuals (aHR, 1.15; 95% CI, 1.10-1.20; P < .001 for interaction). Mortality due to cardiovascular diseases was increased (aHR, 1.21; 95% CI, 1.13-1.29), as was mortality due to cancer (aHR, 1.54; 95% CI, 1.42-1.67). The association between NFAA and mortality remained significant and of similar magnitude in all sensitivity analyses. Conclusions and Relevance: The results of this case-control study suggest that NFAA was associated with an increased overall mortality and mortality of cardiovascular disease and cancer. The increase was more pronounced among younger individuals.

Tuberculosis of Adrenal Glands-A Population-based Case-control Study.

Purpose: Adrenal tuberculosis (ATB) can cause primary adrenal insufficiency (PAI) or may be misdiagnosed as nonfunctional adrenal tumors (NFATs) in patients with tuberculosis. Very little is known about its epidemiology in a modern, high-income setting. The aim was to investigate adrenal involvement and associated mortality in patients with tuberculosis. Methods: By using national registers, patients with tuberculosis and adrenal lesions were compared with controls without adrenal tumors. To analyze mortality in individuals with ATB or possible adrenal affection (ie, tuberculosis and NFAT), a subgroup of controls with tuberculosis was selected. The study population was included from 2005 to 2019 and followed until death or 2020. In mortality adjustments were made for age and sex. Results: Eight patients with ATB, 23 232 patients with NFAT, and 144 124 controls were included. Among those with NFAT, we found 34 with tuberculosis and NFAT. Among controls, 129 individuals diagnosed with tuberculosis were identified. The risk of having an adrenal tumor was increased in tuberculosis (odds ratio, 1.64; 95% CI, 1.12-2.39). Of those with ATB, 7 (88%) had PAI. One patient (3%) with tuberculosis and NFAT and 1 (0.8%) control with tuberculosis had PAI. Compared with controls with tuberculosis, mortality was increased in patients with ATB (hazard ratio, 5.4; 95% CI, 2.2-13.2; adjusted hazard ratio, 6.2; 95% CI, 2.5-15.6), and in patients with tuberculosis and NFAT (1.3; 0.6-2.7; 2.3; 1.1-5.1). PAI was a contributing factor in 4/6 (67%) deaths in patients with ATB. Conclusions: Tuberculosis with adrenal lesions was extremely rare. Most patients with ATB had PAI and mortality was increased.

Adherence to endocrine therapy in early breast cancer in relation to Cytochrome P450 2D6 genotype: a comparison between pharmacy dispensation data and medical records.

PURPOSE: Suboptimal adherence to adjuvant endocrine treatment (AET) is an important clinical concern. A correlation between CYP2D6 activity and tamoxifen discontinuation has been described. The main aim of this study was to investigate the consistency between pharmacy dispensation data and medical records on adherence to AET. METHODS: Adherence was calculated for patients with at least 4.5 years of follow up and was defined as Medical Possession Rate ≥ 80%. Subgroup analyses were performed based on menopausal status, recurrence risk and CYP2D6 activity. RESULTS: In 86% of the 1235 included patients the consistency between the two sources of information was within 80-125%. Poor consistency, < 80%, was most frequent in the premenopausal/ high-risk group and CYP2D6 Poor Metabolizers (PMs). Among 899 patients with at least 4.5 years follow up, 72% were adherent to tamoxifen based on pharmacy dispensation data, compared with 77% as reported by medical records. When including patients who switched to aromatase inhibitors after tamoxifen, adherence increased to 82% and 88%, respectively. Adherence did not differ by menopausal status or risk for recurrence. CYP2D6 PMs had poorer adherence (54%) to tamoxifen compared to patients with the highest CYP2D6 activity (83%). CONCLUSIONS: There was a good consistency between medical records and pharmacy dispensing data on the use of AET. Adherence to AET was adequate, especially when including switch to aromatase inhibitors. Surprisingly, CYP2D6 PMs had low adherence to tamoxifen, despite a likely reduced risk of side effects according to previous data.

Time-dependent association between omeprazole and esomeprazole and hospitalization due to hyponatremia.

PURPOSE: The aim of this study was to explore the time-course of hospitalization due to hyponatremia associated with omeprazole and esomeprazole. METHODS: In this register-based case-control study, we compared patients hospitalized with a main diagnosis of hyponatremia (n = 11,213) to matched controls (n = 44,801). We used multiple regression to investigate time-related associations between omeprazole and esomeprazole and hospitalization because of hyponatremia. RESULTS: The overall adjusted OR (aOR) between proton pump inhibitor (PPI) exposure, regardless of treatment duration and hospitalization with a main diagnosis of hyponatremia, was 1.23 (95% confidence interval CI 1.15-1.32). Exposure to PPIs was associated with a prompt increase in risk of hospitalization for hyponatremia from the first week (aOR 6.87; 95% CI 4.83-9.86). The risk then gradually declined, reaching an aOR of 1.64 (0.96-2.75) the fifth week. The aOR of ongoing PPI treatment was 1.10 (1.03-1.18). CONCLUSION: The present study shows a marked association between omeprazole and esomeprazole and hyponatremia related to recently initiated treatment. Consequently, newly initiated PPIs should be considered a potential culprit in any patient suffering from hyponatremia. However, if the patient has had this treatment for a longer time, the PPI should be considered a less likely cause.

Current and Future Burdens of Heat-Related Hyponatremia: A Nationwide Register-Based Study.

CONTEXT: A seasonal variation in hyponatremia, with higher incidence rates during hot summer days, has been demonstrated. Whether this applies to cool temperate regions is currently unknown. OBJECTIVE: The aim of this study was to investigate the influence of ambient temperature on hyponatremia in the Swedish population under current and future climate scenarios. METHODS: This nationwide cohort study identified all patients hospitalized with a first-ever principal diagnosis of hyponatremia between October 2005 and December 2014. Incidence rates for hyponatremia were calculated as number of hospitalizations divided by person-days at risk in the adult Swedish population at a given temperature, in increments of 1 °C. RESULTS: The incidence of hyponatremia was stable at 0.3 per million person-days from -10 to 10 °C, but increased rapidly at 24-hour mean temperatures above 15 °C, with 2.26 hospitalizations per million days at the highest recorded temperature of 25 °C. Women and elderly carried the greatest risk, with an incidence of 35 hospitalizations per million days in individuals ≥ 80 years of age on the hottest days, corresponding to a 15-fold increase in incidence compared with cool days. A future 1 or 2 °C increase in mean temperature is expected to increase the incidence of hyponatremia by 6.3% and 13.9%, respectively. CONCLUSION: The risk of hospitalization due to hyponatremia increases rapidly at temperatures above 15 °C, indicating a threshold effect. Over the next decades, rising global temperatures are expected to increase the inpatient burden of hyponatremia by approximately 10%. Strategies for protecting vulnerable groups are necessary to reduce this risk.

Impact of systemic adjuvant therapy and CYP2D6 activity on mammographic density in a cohort of tamoxifen-treated breast cancer patients.

PURPOSE: Change in mammographic density has been suggested to be a proxy of tamoxifen response. We investigated the effect of additional adjuvant systemic therapy and CYP2D6 activity on MD change in a cohort of tamoxifen-treated pre- and postmenopausal breast cancer patients. METHODS: Swedish breast cancer patients (n = 699)  operated 2006-2014, genotyped for CYP2D6, having at least three months postoperative tamoxifen treatment, a baseline, and at least one follow-up digital mammogram were included in the study. Other systemic adjuvant treatment included chemotherapy, goserelin, and aromatase inhibitors. Change in MD, dense area, was assessed using the automated STRATUS method. Patients were stratified on baseline characteristics, treatments, and CYP2D6 activity (poor, intermediate, extensive, and ultrarapid). Relative density change was calculated at year 1, 2, and 5 during follow-up in relation to treatments and CYP2D6 activity. RESULTS: Mean relative DA decreased under the follow-up period, with a more pronounced MD reduction in premenopausal patients. No significant effect of chemotherapy, aromatase inhibitors, goserelin, or CYP2D6 activity on DA change was found. DA did not revert to baseline levels after tamoxifen discontinuation. CONCLUSION: Our results indicate that other systemic adjuvant therapy does not further reduce MD in tamoxifen-treated breast cancer patients. We could not confirm the previously suggested association between CYP2D6 activity and MD reduction in a clinical setting with multimodality adjuvant treatment. No rebound effect on MD decline after tamoxifen discontinuation was evident.

Non-thiazide diuretics and hospitalization due to hyponatraemia: A population-based case-control study.

OBJECTIVE: Diuretics are often implicated in hyponatraemia. While thiazides constitute one of the most common causes of hyponatraemia, data on loop diuretics and potassium-sparing agents are limited and partly conflicting. The objective of this investigation was to study the association between use of different types of non-thiazide diuretics and hospitalization due to hyponatraemia. DESIGN, PATIENTS AND MEASUREMENTS: This was a register-based case-control study on the adult Swedish population. By linking national registers, patients hospitalized with a principal diagnosis of hyponatraemia (n = 11,213) from 1 October 2005 through 31 December 2014 were compared with matched controls (n = 44,801). Multivariable logistic regression, adjusted for multiple confounders, was used to analyse the association between use of diuretics and hyponatraemia. In addition, newly initiated use (≤90 days) and ongoing use were examined separately. RESULTS: Adjusted odds ratios (aORs) (95% CI) were 0.61 (0.57-0.66) for the use of furosemide, 1.69 (1.54-1.86) for the use of amiloride and 1.96 (1.78-2.18) for the use of spironolactone and hospitalization due to hyponatraemia. For newly initiated therapy, aORs ranged from 1.23 (1.04-1.47) for furosemide to 3.55 (2.75-4.61) for spironolactone. The aORs for ongoing use were 0.52 (0.47-0.57) for furosemide, 1.62 (1.47-1.79) for amiloride and 1.75 (1.56-1.98) for spironolactone. CONCLUSIONS: Ongoing use of furosemide was inversely correlated with hospitalization due to hyponatraemia, suggesting a protective effect. Consequently, if treatment with furosemide precedes the development of hyponatraemia by some time, other causes of hyponatraemia should be sought. Spironolactone and amiloride may both contribute to hyponatraemia; this effect is most prominent early in treatment.

Time-dependent association between selective serotonin reuptake inhibitors and hospitalization due to hyponatremia.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) have a wide and increasing use for the treatment of depression and anxiety. Previous studies have indicated an increased risk of hyponatremia during the first months of treatment. We aimed to investigate the detailed time-course of SSRI-associated hyponatremia with a high temporal resolution, using registry data encompassing the total Swedish population. METHODS: This was a population-based case control study using several national registers. Patients hospitalized with a principal diagnosis of hyponatremia (n = 11,213) were compared with matched controls (n = 44,801). Multivariable regression was applied to explore time-dependent associations between SSRIs and hospitalization due to hyponatremia. RESULTS: Individuals initiating treatment with SSRIs were exposed to an immediately increased risk for hospitalization at week 1, reaching an adjusted odds ratio (aOR) (95% confidence interval) of 29 (19-46). The associations then gradually declined, reaching an aOR of 2.1 (1.0-4.2) by week 13. The aOR for individuals treated for longer than 13 weeks was 0.78 (0.71-0.85). CONCLUSIONS: This study revealed a dramatically increased risk of hyponatremia exclusively related to newly initiated treatment. Consequently, even subtle symptoms consistent with hyponatremia during the first weeks of SSRI treatment should prompt analysis of sodium levels. In patients treated with SSRIs for several months or years, other causes should primarily be sought in the event of hyponatremia.

Association between newly initiated thiazide diuretics and hospitalization due to hyponatremia.

PURPOSE: Thiazide diuretics are the most common origin of drug-induced hyponatremia. However, population-based studies on clinical outcomes are lacking. We therefore explored the time course and absolute risk of thiazide-associated hospitalization due to hyponatremia in Sweden. METHODS: Population-based case-control study including patients hospitalized with a principal diagnosis of hyponatremia (n = 11,213) compared with controls (n = 44,801). Linkage of registers was used to acquire data. Multivariable regression was applied to explore time-dependent associations between thiazide diuretics and hospitalization due to hyponatremia. Attributable risks were calculated assessing the disease burden attributable to thiazides. RESULTS: Individuals initiating thiazide treatment were exposed to an immediate increase in risk for hospitalization with adjusted odds ratio (aOR) (95% CI) of 48 (28-89). The associations gradually declined reaching an aOR of 2.9 (2.7-3.1) for individuals treated for longer than 13 weeks. The attributable risk of hyponatremia-associated hospitalization due to thiazides of any treatment length was 27% (3095/11,213). Among 806 patients initiating treatment < 90 days before hospitalization, hyponatremia could be attributed to thiazides in 754. Based on nationwide data, 616,678 individuals were initiated on thiazides during the 8-year study period suggesting an absolute risk of 0.12% (754/661,678) for subsequent hospitalization with a main diagnosis of hyponatremia. CONCLUSIONS: Thiazide diuretics attributed to more than one in four individuals hospitalized due to hyponatremia. The risk increase was very pronounced during the first month of treatment and then gradually declined, without returning to normal. However, the absolute risk for the development of hyponatremia demanding hospitalization may for most individuals be modest.

Impairment of endoxifen formation in tamoxifen-treated premenopausal breast cancer patients carrying reduced-function CYP2D6 alleles.

AIMS: Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6-dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects. METHODS: In total, 118 Swedish premenopausal breast cancer patients diagnosed 2006-2014, with on-going postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real-time polymerase chain reaction (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and 3 major metabolites were quantified by liquid chromatography-tandem mass spectrometry. Clinical information on treatment and side effects was retrospectively obtained from medical records. RESULTS: In the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6-5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with 2 reduced-function alleles, 2 null-alleles, or a null/reduced-function combination. CYP2D6*41 was the most common reduced-function allele (82%) and 17 of 21 CYP2D6*41-carriers exhibited a lower CYP2D6 activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of 2 null-alleles vs patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (P = .338). In patients with endoxifen levels <5.9 ng/mL (36/114), side effects were either mild or absent. At higher endoxifen levels moderate-to-severe side effects were reported in a concentration-dependent manner. CONCLUSION: Significantly reduced endoxifen levels were observed not only in all homozygous carriers of CYP2D6 null-alleles, but also in carriers of 2 reduced-function alleles. This finding may be highly relevant for future, genotype-based dose considerations.

Bleeding and thromboembolism due to drug-drug interactions with non-vitamin K antagonist oral anticoagulants-a Swedish, register-based cohort study in atrial fibrillation outpatients.

PURPOSE: To study the association between interacting drugs and bleeding or thromboembolism in atrial fibrillation outpatients treated with non-vitamin K antagonist oral anticoagulants (NOACs). METHODS: Population-based cohort study of outpatients treated with NOACs in Sweden from 2008 to 2017. Patients with atrial fibrillation and newly initiated NOAC treatment were identified in the Prescribed Drug Register. Comorbidities and outcome data were retrieved from the Patient Register and the Cause of Death Register. Cox-regression analyses were performed to evaluate the primary endpoints any severe bleed and ischemic stroke/transient ischemic attack/stroke unspecified during the first six months of treatment. Secondary endpoints were gastrointestinal bleeding, intracranial bleeding, ischemic stroke, and venous thromboembolism. RESULTS: Increased risk of any severe bleed was found when NOAC treatment, and drugs with pharmacodynamic effect on bleeding were combined, compared to NOAC only. An increased risk with these combinations was evident for apixaban (hazard ratio (HR) 1.47; 95% CI 1.33-1.63), rivaroxaban (HR 1.7; 95% CI 1.49-1.92), and dabigatran (HR 1.26; 95% CI 1.05-1.52). For apixaban, there was an increased risk of any severe bleed when combined with CYP3A4 and/or P-glycoprotein (P-gp) inhibitors (HR 1.23; 95% CI 1.01-1.5). The use of inducers of CYP3A4 and/or P-gp was low in this cohort, and effects on ischemic stroke/TIA/stroke unspecified could not be established. CONCLUSION: Increased risk of bleeding was seen for pharmacodynamic and pharmacokinetic interactions with NOACs. Prescribers need to be vigilant of the effect of interacting drugs on the risk profile of patients treated with NOACs.

Reduced risk for hospitalization due to hyponatraemia in lithium treated patients: A Swedish population-based case-control study.

BACKGROUND: Many drugs used in psychiatry have been reported to cause hyponatraemia. However, lithium may be an exception due to its potential for causing nephrogenic diabetes insipidus, but clinical data are largely absent. The objective of this investigation was to study the association between lithium therapy and hospitalization due to hyponatraemia. METHODS: This study was a register-based case-control investigation of the general Swedish population. Patients hospitalized with a principal diagnosis of hyponatraemia (n=11,213) were compared with matched controls (n=44,801). Analyses using multivariable logistic regression adjusting for co-medication, diseases, previous hospitalizations and socioeconomic factors were deployed to calculate the association between severe hyponatraemia and the use of lithium. Additionally, newly initiated (⩽90 days) and ongoing lithium therapy was studied separately. RESULTS: Compared with controls, the unadjusted odds ratio (OR) (95% confidence interval (CI)) for hospitalization due to hyponatraemia was 1.07 (0.70-1.59) for lithium. However, after adjustment for confounding factors the risk was reduced (adjusted OR: 0.53 (0.31-0.87)). Newly initiated lithium therapy was not significantly associated with hyponatraemia (adjusted OR 0.73 (0.35-5.38)). In contrast, for ongoing therapy the corresponding adjusted OR was significantly reduced (adjusted OR: 0.52 (0.30-0.87)). CONCLUSIONS: A marked inverse association was found between ongoing lithium therapy and hospitalization due to hyponatraemia.