In this prospectively enrolled cohort, we found more than a quarter of PA patients concomitant with ACS. Our study suggested that 24-h UFC less than 36 µg was a cut-off point in exclusion of the patient that is possible ACS in patients with PA. Additionally, older age and diabetes mellitus were also risk factors for predicting ACS in PA patients. (supplementary Fig. 1)
Autonomous cortisol secretion, of which biochemical tests showed cortisol hypersecretion without clinical manifestations, had a high prevalence in PA patients. The presence of concomitant ACS in patients with primary aldosteronism (PA) was linked to more severe metabolic syndrome, as well as severe left ventricular hypertrophy and poor renal function [2, 7, 8]. A previous study demonstrated a significant correlation between glucocorticoid excess and various metabolic risk factors, such as waist circumference, high-density lipoprotein, and diastolic blood pressure. Furthermore, the study showed that body mass index and insulin resistance, both of which are associated with obesity, were also affected by glucocorticoid excess. These findings suggest that the previously unidentified glucocorticoid excess in primary aldosteronism is a significant contributor to metabolic risk. [5]. Therefore, in such patients, it is important to figure out if there was excess cortisol secretion and 24-h UFC had shown to be useful to discriminate if there was excess cortisol secretion in the diagnosis of ACS [24].
The accuracy of overnight 1 mg DST can be influenced by the variable absorption and metabolism of dexamethasone. Factors such as concomitant use of drugs or alcohol, which can induce hepatic enzymes through CYP3A4, may lead to a reduction in dexamethasone levels. In addition, dexamethasone levels can vary significantly among healthy individuals who are not taking the drug. To mitigate the risk of false-positive or false-negative reactions, performing different types of examinations or repeating the measurement could help increase confidence in the test results.
24-h UFC provided a directed index of cortisol secretion. A previous study including Cushing's disease revealed that the 24-h UFC with 150 µg as a cut-off point in diagnosis of Cushing's disease had a sensitivity of 78.8% and a specificity of 52.5% [25], while in a previous meta-analytic study, the UFC was less sensitive compared to the other diagnostic tests in Cushing's syndrome with a sensitivity of 94.0% and a specificity of 93.0% [26]. In contrast to previous studies, our investigation comprised patients with primary aldosteronism (PA), while also excluding individuals who may have had hypercortisolism without Cushing's syndrome, such as those who were pregnant, had depression, alcohol dependence, or poorly controlled diabetes [27, 28]. Patients with Cushing's disease exhibited a higher midnight serum cortisol concentration compared to those without the disease. In our study, we also observed that patients with elevated urine-free cortisol levels had higher midnight cortisol levels, which could serve as an additional useful indicator of cortisol secretion.
A previous retrospective study identified a 24-hour urine-free cortisol (UFC) cut-off point of 70 µg for predicting adrenal cortical adenomas (ACS) with a sensitivity of 15.8%, specificity of 91.7%, positive predictive value (PPV) of 54.5%, and negative predictive value (NPV) of 63.4% [29]. However, this study also showed poor sensitivity in diagnosing ACS in the evaluation of adrenal incidentalomas. In contrast, our study demonstrated a higher NPV at a 24-hour UFC cut-off point of 36 µg, indicating that a daily urinary cortisol level of ≤ 36 µg could exclude the diagnosis of ACS in patients with PA. Our study also showed that diabetes mellitus and older age were also risk factors for predicting ACS in PA patients. The previous studies revealed a higher prevalence of diabetes mellitus in PA patients with ACS [30, 31] and a higher prevalence of ACS in older patients with adrenal incidentalomas [32–34]. In addition, about 15% of adrenal incidentalomas were associated with hormone secretion [35], which may also explain why age could be a risk factor for ACS, implying valuable insight into predicting ACS in PA patients.
Our study has some limitations and most of which are attributable to its data collection. The data from the Taiwan Primary Aldosteronism Investigation (TAIPAI) registry only recruited patients with a suspected PA diagnosis, which may cause selection bias. However, we included all consecutive patients who met the inclusion criteria of PA during the study period, ensuring comparable laboratory results. We also excluded patients who had known factors associated with false positive DST results, such as oral hormone contraceptive use, drug treatments that affect dexamethasone metabolism, liver disease, and psychiatric illness. However, the generalizability of our findings may be limited, as the database was constructed from medical centers and regional hospitals located in different cities in Taiwan. Factors such as income levels, race, ethnicity, and cultural practices in other countries may not be similar, which may affect the applicability of our results.