Mortality Not Increased in Patients With Nonfunctional Adrenal Adenomas: A Matched Cohort Study.

CONTEXT: Mild autonomous cortisol secretion (MACS) is associated with increased mortality in patients with adrenal incidentalomas, but little is known regarding the potential risk associated with nonfunctional adrenal adenomas (NFAA), which constitute the majority of adrenal incidentalomas. OBJECTIVE: Compare mortality risk in patients with NFAA, and different levels of MACS, to matched controls. METHOD: This was a retrospective matched cohort study. All patients referred to 2 endocrine centers in southern Sweden because of an adrenal incidentaloma between 2005 and 2015 were enrolled. Controls (3:1) matched for sex, age, and residency were included. Primary endpoint was all-cause mortality. Outcome data were obtained from the Cause of Death Register. Patients were grouped according to cortisol level post 1-mg dexamethasone suppression test (cortisolDST) (<50 (NFAA), 50-82, 83-137, and ≥138 nmol/L). RESULTS: 1154 patients and 3462 matched controls were included. During a median follow-up of 6.6 years, 210 patients and 505 controls died. There were no statistically significant differences in mortality between patients with NFAA and their controls (HR 1.13 [0.87-1.46]) whereas mortality was increased compared to controls in patients with cortisolDST 83-137 (HR 1.99 [1.38-2.88]) and ≥138 nmol/L (HR 4.09 [2.41-6.93]). Likewise, the mortality risk was increased in patients younger than 65 years with cortisolDST 50-82 nmol/L compared with controls (HR 2.33 [1.30-4.17]). CONCLUSION: NFAA does not seem to pose a clinically relevant risk for increased mortality in patients with adrenal incidentalomas while patients with MACS, and especially younger patients and those with cortisolDST ≥83 nmol/L, have significantly increased mortality risk compared with matched controls.

Association Between Mortality and Levels of Autonomous Cortisol Secretion by Adrenal Incidentalomas : A Cohort Study.

BACKGROUND: Autonomous cortisol secretion in patients with adrenal incidentalomas is associated with increased mortality, but detailed information about the risk associated with specific levels of autonomous cortisol secretion is not available. OBJECTIVE: To measure the association between mortality and levels of autonomous cortisol secretion in patients with adrenal incidentalomas. DESIGN: Retrospective cohort study. (ClinicalTrials.gov: NCT03919734). SETTING: Two hospitals in southern Sweden. PATIENTS: Consecutive patients who had adrenal incidentalomas identified between 2005 and 2015 and were followed for up to 14 years. Outcome data were collected from national registers. MEASUREMENTS: Patients were grouped according to plasma cortisol level after a 1-mg dexamethasone suppression test (cortisolDST; <50, 50 to 82, 83 to 137, or ≥138 nmol/L). RESULTS: During a median follow-up of 6.4 years, 170 of 1048 patients died. Compared with a cortisolDST less than 50 nmol/L, a cortisolDST of 50 to 82 nmol/L was not associated with increased mortality (hazard ratio [HR], 1.15 [95% CI, 0.78 to 1.70]). However, a cortisolDST of 83 to 137 nmol/L (n = 119) had an HR of 2.30 (CI, 1.52 to 3.49), and a cortisolDST of 138 nmol/L or higher (n = 82) had an HR of 3.04 (CI, 1.86 to 4.98). Analyses using restricted cubic splines indicated that the association between cortisolDST and mortality was linear up to a cortisolDST of 200 nmol/L. LIMITATION: The results are not based on verified autonomous cortisol secretion; thus, the association may be underestimated. CONCLUSION: The association between mortality and cortisolDST increased linearly until cortisolDST reached 200 nmol/L. A cortisolDST of 83 to 137 nmol/L was associated with a 2-fold increase in mortality, and a cortisolDST of 138 nmol/L or higher was associated with a 3-fold increase in mortality. Additional studies should be done, and until those studies are completed some clinicians may consider these findings when deciding which patients to recommend for surgery. PRIMARY FUNDING SOURCE: Lisa and Johan Grönberg Foundation and Gyllenstiernska Krapperup Foundation.

ACTH following overnight dexamethasone suppression can be used in the verification of autonomous cortisol secretion in patients with adrenal incidentalomas.

OBJECTIVE: During the investigation of adrenal incidentalomas, it is important to accurately diagnose autonomous cortisol secretion (ACS) but the specificity of cortisol ≥50 nmol/L after overnight dexamethasone suppression (cortisolONDST ) is low. Therefore, ACTH following overnight dexamethasone suppression (ACTHONDST ) and cortisol following a 2-day dexamethasone suppression test (cortisol2-DAYDST ) were examined as markers of HPA axis suppression during ONDST. DESIGN: This cross-sectional study examined patients with adrenal incidentalomas and basal ACTH ≥ 2.0 pmol/L who underwent ONDST. MEASUREMENTS: ACTHONDST /ACTH ratio (ACTH ratio) was calculated for all patients. To define cut-off levels for ACTHONDST and ACTH ratio as markers of HPA axis suppression, ROC curves were used to separate patients with cortisolONDST <50 and ≥50 nmol/L. RESULTS: CortisolONDST was ≥50 nmol/L in 140 out of 373 patients. In patients with cortisolONDST <50 nmol/L, ACTHONDST was 0.28 pmol/L (<0.23-2.7). DHEAS was positively correlated to ACTHONDST , demonstrating a 9% increase with a doubling in ACTHONDST , p = 0.02. The best cut-off levels for ACTHONDST and ACTH ratio to detect cortisolONDST ≥50 nmol/L were ≥0.6 pmol/L and ≥18% respectively. These cut-off levels were tested on patients with cortisolONDST <50 nmol/L, considered to have adequate suppression (n = 233), and patients with reduction of ≥50 nmol/L from cortisolONDST to cortisol2-DAYDST , who were considered to have inadequate suppression (n = 16). ACTHONDST ≥0.6 pmol/L and ACTH ratio ≥18% had a sensitivity of 75% and 81% respectively, and a specificity of 78% and 85% respectively, for detecting patients with inadequate suppression. CONCLUSIONS: ACTHONDST and ACTH ratio can be markers of HPA axis suppression in the investigation of adrenal incidentalomas. CortisolONDST ≥50 nmol/L with ACTHONDST <0.6 pmol/L or ACTH ratio <18% should lead to the suspicion of ACS.

High prevalence of smoking in patients with adrenal incidentalomas: causality or case selection?

OBJECTIVE: Autonomous cortisol secretion and possible autonomous cortisol secretion (ACS/pACS) are associated to an increase of cardiovascular risk factors such as hypertension, diabetes mellitus and dyslipidaemia. To our knowledge, the prevalence of smoking, another well-established risk factor for cardiovascular disease, has not been studied in detail in people with ACS/pACS or adrenal incidentalomas. METHODS: Patients with adrenal incidentalomas were examined with the 1-mg overnight dexamethasone suppression test (cortisolONDST). Information about current smoking was collected from the patient's records. RESULTS: We studied 1044 patients, of whom 370 (35%) were current smokers. Of these, 22% had bilateral AI compared to 12% of the non-smokers (P < 0.001). Among patients with unilateral adrenal incidentalomas, smokers had larger adrenal incidentalomas than non-smokers (22 mm vs 19 mm, P < 0.001). Smokers also more often had cortisolONDST ≥50 nmol/L than non-smokers, 54% vs 40% (P < 0.001), a finding independent of the size of the adrenal incidentaloma in patients with unilateral adrenal incidentalomas. CONCLUSIONS: In the present study of patients with adrenal incidentalomas, the prevalence of current smoking was higher than in the general population. Furthermore, smokers had larger unilateral adrenal incidentalomas, more often bilateral adrenal incidentalomas, and more frequently ACS/pACS. Whether smoking is a risk factor for adrenal incidentalomas and ACS/pACS or our findings are due to case selection needs to be further studied.

Suppressed ACTH Is Frequently Unrelated to Autonomous Cortisol Secretion in Patients With Adrenal Incidentalomas.

Objective: ACTH is considered a weak marker for autonomous cortisol secretion (ACS) in patients with adrenal incidentalomas (AIs). Our aim was to investigate suppressed basal ACTH as a marker of ACS and to elucidate why this criterion is of limited value. Methods: Basal ACTH and cortisol after overnight dexamethasone suppression test (cortisolONDST) were measured in 198 patients with unilateral AI and at 2-year follow-up. Basal ACTH was measured in 100 control subjects. Results: In patients with cortisolONDST <50 nmol/L (n = 145), ACTH was <2 pmol/L in 19%, compared with 4% in control subjects (P < 0.001). ACTH and size of AI correlated negatively (P = 0.002). Among patients with cortisolONDST ≥50 nmol/L, ACTH was <2 pmol/L in 53%. The patients were grouped according to whether cortisolONDST was <50 or ≥50 nmol/L and whether ACTH was <2.0 or ≥2.0 or pmol/L. At follow-up, these four groups were still separated with statistically significant differences in ACTH and cortisolONDST. Conclusions: This study identifies a previously unrecognized group of patients defined by suppressed ACTH despite normal cortisolONDST. This suppression of ACTH by a factor other than ACS may explain the limitation of suppressed ACTH as a marker for ACS. We suggest increased cortisol secretion in response to ACTH by the AI to be an additional factor.