Plasma Free Cortisol in States of Normal and Altered Binding Globulins: Implications for Adrenal Insufficiency Diagnosis

• Published in: The journal of clinical endocrinology and metabolism Vol. 104; no. 10; pp. 4827 - 4836
• Main Authors: Dichtel, Laura E, Schorr, Melanie, Loures de Assis, Claudia, Rao, Elizabeth M, Sims, Jessica K, Corey, Kathleen E, Kohli, Puja, Sluss, Patrick M, McPhaul, Michael J, Miller, Karen K
• Format: Journal Article
• Language: English
• Published: Washington, DC Endocrine Society 01.10.2019; Copyright Oxford University Press; Oxford University Press
• Subjects: Administration, Oral; Adrenal glands; Adrenal Insufficiency - blood; Adrenal Insufficiency - diagnosis; Adult; Aged; Albumin; Analysis; Biological products industry; Blood proteins; Carrier Proteins - blood; Chromatography, Liquid; Cirrhosis; Clinical s; Cohort Studies; Contraceptives, Oral, Hormonal - administration & dosage; Contraceptives, Oral, Hormonal - adverse effects; Corticosteroids; Cortisol; Critical Illness; Cross-Sectional Studies; Diagnosis; Enzyme-linked immunosorbent assay; Estrogens - administration & dosage; Estrogens - blood; Female; Globulins; Globulins - analysis; Globulins - metabolism; Hormonal Contraception - adverse effects; Hormone Replacement Therapy - adverse effects; Hormone Replacement Therapy - methods; Hormones; Humans; Hydrocortisone - blood; Liquid chromatography; Liver cirrhosis; Liver Cirrhosis - blood; Male; Mass spectrometry; Mass spectroscopy; Middle Aged; Oral contraceptives; Pituitary-Adrenal Function Tests - standards; Sensitivity and Specificity; Spectrophotometry; Tandem Mass Spectrometry; Young Adult; United States; Massachusetts; California
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2019-00022

Abstract Context Accurate diagnosis of adrenal insufficiency is critical because there are risks associated with overdiagnosis and underdiagnosis. Data using liquid chromatography tandem mass spectrometry (LC/MS/MS) free cortisol (FC) assays in states of high or low cortisol-binding globulin (CBG) levels, including cirrhosis, critical illness, and oral estrogen use, are needed. Design Cross-sectional. Objective Determine the relationship between CBG and albumin as well as total cortisol (TC) and FC in states of normal and abnormal CBG. Establish the FC level by LC/MS/MS that best predicts TC of <18 μg/dL (497 nmol/L) (standard adrenal insufficiency diagnostic cutoff) in healthy individuals. Subjects This study included a total of 338 subjects in four groups: healthy control (HC) subjects (n = 243), patients with cirrhosis (n = 38), intensive care unit patients (ICU) (n = 26), and oral contraceptive (OCP) users (n = 31). Main Outcome Measure(s) FC and TC by LC/MS/MS, albumin by spectrophotometry, and CBG by ELISA. Results TC correlated with FC in the ICU (R = 0.91), HC (R = 0.90), cirrhosis (R = 0.86), and OCP (R = 0.70) groups (all P < 0.0001). In receiver operator curve analysis in the HC group, FC of 0.9 μg/dL (24.8 nmol/L) predicted TC of <18 μg/dL (497 nmol/L; 98% sensitivity, 91% specificity; AUC, 0.98; P < 0.0001). Decreasing the cutoff to 0.7 μg/dL led to a small decrease in sensitivity (92%) with similar specificity (91%). Conclusions A cutoff FC of <0.9 μg/dL (25 nmol/L) in this LC/MS/MS assay predicts TC of <18 μg/dL (497 nmol/L) with excellent sensitivity and specificity. This FC cutoff may be helpful in ruling out adrenal insufficiency in patients with binding globulin derangements. In healthy subjects, plasma free cortisol of 0.9 μg/dL best predicted total cortisol of <18 μg/dL and could aid in the diagnosis of adrenal insufficiency in states of altered binding globulins.