Utility of Urinary Ratio of Cortisol to Aldosterone as Inflammatory and Metabolic Parameters

Corticosteroids are important bioactive substances in the body that regulate inflammation, metabolism, immunity, and circulatory dynamics. Cortisol and aldosterone are two major naturally occurring steroids, which synthesized in the adrenal fasciculata and in the adrenal glomerulosa under the regulation of adrenocorticotropin (ACTH) and renin-angiotensin system (RAS), respectively. The conventional strategy for evaluating adrenocortical function has been to measure random serum cortisol or 24-hour stored levels of urine free cortisol (UFC). UFC is a more appropriate marker to avoid the effects of diurnal fluctuation of cortisol, serum cortisol-binding proteins, and cortisol clearance in the kidney. Thus, measurement of UFC has been a reliable test for diagnosis of Cushing’s disease or adrenal insufficiency. However, since the normal range of UFC varies widely, it is often difficult to evaluate whether the UFC level is optimal or not for each patient. That is because UFC is greatly affected by the amount of fluid intake or urine volume, and an immunoassay for UFC, which is the usual method for measuring UFC, is susceptible to interference from other steroid metabolites and synthetic glucocorticoids. To explore an alternative indicator, we tried to standardize the levels of UFC by the levels of urinary aldosterone concentration (UAC) in the same urinary sample. Medical records of all 246 patients in whom daily excretions of UFC and UAC had been measured between 2015 and 2018 at our department were reviewed. 142 patients (including 93 females) were included after exclusion of 104 patients because of corticosteroid replacement therapy. UFC/UAC ratio showed significant positive and negative correlations with the levels of serum cortisol (R=0.287) and aldosterone (R=-0.762), respectively. UFC/UAC ratio increased with aging in female patients, while the ratio was not altered by the levels of BMI in either gender. Markers for metabolic and inflammatory status including hemoglobin A1c (R=0.327), albumin (R=-0.331), chorine esterase (R=-0.248), C-reactive protein (R=0.317), ferritin (R=0.473), and D-dimer (R=0.569) showed correlations to the ratio of UFC/UAC that were more significant than the correlations to the serum level of cortisol or UFC alone. Of note, the UFC/UAC ratio was shown as an indicator for risks of diabetes (AUC: 0.765), hypoalbuminemia (0.839), hyper-CRPemia (0.748), and thrombophilia (0.824), in which the cut-off levels of UFC/UAC ratios were found to be around 12. These results indicate that the UFC/UAC ratio is a suitable variable for the detection of metabolic and inflammatory complications related to adrenocortical dysfunction.