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.

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.

Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study.

BACKGROUND: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). METHODS: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. FINDINGS: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). INTERPRETATION: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. FUNDING: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino.

Increased mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: a 13-year retrospective study from one center.

PURPOSE: To compare long-term outcomes in patients with adrenal incidentalomas (AIs) with the response to a 1 mg overnight dexamethasone suppression test (DST). METHODS: Consecutive patients with "non-functional" AIs (n = 365) were examined. Patients with overt hormone excess, adrenocortical cancer and known malignancy had been excluded. Patients were classified to normal cortisol secretion group (n = 204, DST ≤ 50 nmol/l), possible autonomous cortisol secretion group (n = 128, DST 51-138 nmol/l) and autonomous cortisol secretion group (n = 33, DST ≥ 138 nmol/l). RESULTS: Thirty-seven patients (10.1%) deceased during the follow-up period (5.2 ± 2.3 years): 16(7.8%) in the non-secreting group (time from diagnosis to death: 3.9 ± 2.9 years), 15 in the possible autonomous cortisol secretion group (11.7%, 3.2 ± 1.8 years) and 6 in the autonomous cortisol secretion group (18.2%, 2.3 ± 1.5 years), respectively (P = 0.019). Multivariate analysis only found significant association with age and the tumour size but if cortisol levels post-DST were analysed as a continuous variable it was significant as well. All deaths in autonomous cortisol secretion group were due to cancer not related to adrenal glands. Hypertension, cardiovascular disease and medications were more common in the possible and autonomous cortisol secretion group, especially in the former. More bilateral AIs and larger AI size were found in the two latter groups. CONCLUSIONS: Patients with autonomous cortisol secretion had higher mortality than those with non-functioning AIs though cortisol levels post-DST as a continuous variable, age and tumour size were better predictor of mortality. Cardiovascular disease and osteoporosis medication seemed more prevalent in the possible and autonomous cortisol secretion groups, especially in the former.

CLINICAL OUTCOMES IN ADRENAL INCIDENTALOMA: EXPERIENCE FROM ONE CENTER.

OBJECTIVE: To investigate the outcome in patients with adrenal incidentaloma (AI). METHODS: A retrospective evaluation of 637 patients with AI referred to a tertiary center over 8 years. Radiologic and hormonal evaluations were performed at baseline. Follow-up imaging was carried out if necessary, and hormonal evaluation was performed at 24 months according to national guidelines. RESULTS: The mean age was 62.7 ± 11.6 years, and the mean AI size was 25.3 ± 17.0 mm at presentation. Hormonal evaluation revealed that 85.4% of all tumors were nonfunctioning adenomas, 4.1% subclinical Cushing syndrome (SCS), 1.4% pheochromocytoma, 1.4% primary hyperaldosteronism, 0.8% Cushing syndrome, 0.6% adrenocortical carcinoma, 0.3% congenital adrenal hyperplasia, 2.2% metastasis to adrenals, and 3.8% other lesions of benign origin. Bilateral tumors were found in 11%, and compared to unilateral tumors, SCS was more prevalent. Only 2 cases were reclassified during follow-up, both as SCS, but neither had had a dexamethasone suppression test performed at initial work-up. In patients diagnosed with an adrenal metastasis, 92.9% were deceased within 2 years. Excluding those with malignant tumors, 12.9% of patients died during the study period of up to 11 years due to other causes than adrenal. CONCLUSION: Most AIs were benign, but a small fraction of tumors were functional and malignant. The prognosis of patients with adrenal metastasis was extremely poor, but otherwise, the mortality rate was similar to that for the general population. Follow-up of AIs <4 cm with an initial nonfunctional profile and benign radiologic appearance appears unwarranted, but screening for congenital adrenal hyperplasia should be considered.