Pyrexia's effect on the CBG-cortisol thermocouple, rather than CBG cleavage, elevates the acute free cortisol response to TNF-α in humans.

Corticosteroid-binding globulin (CBG) cleavage promotes local cortisol delivery in inflammation. Enzymatic cleavage of high-affinity CBG to low-affinity CBG (haCBG to laCBG) occurs at inflammatory sites and is now measurable in vivo; however, the time kinetics of haCBG depletion following an inflammatory stimulus is unknown. Hence our aim was to determine the immediate effect of the key pro-inflammatory cytokine TNF-α on CBG levels and cleavage. We performed a crossover study of 12 healthy males receiving a TNF-α versus saline infusion, measuring total CBG, haCBG, laCBG and free and total cortisol hourly for 6 h. There was no change in total CBG or haCBG levels in the first 6 h of inflammation between the groups, suggesting that CBG cleavage is not activated nor is hepatic CBG production affected by TNF-α in this time frame. There was an early increase in the ratio of free:total cortisol, in association with pyrexia. This accords with data indicating that CBG acts a thermocouple in vivo, increasing free cortisol levels independent of elastase-driven cleavage.

Cortisol, Stress, and Disease-Bidirectional Associations; Role for Corticosteroid-Binding Globulin?

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.

Corticosteroid-Binding Globulin Deficiency Independently Predicts Mortality in Septic Shock.

CONTEXT: Hydrocortisone administration in septic shock remains controversial. Corticosteroid-binding globulin (CBG) transports cortisol to inflammatory sites and is depleted in septic shock. OBJECTIVE: To determine whether severely deficient serum CBG < 200 nmol/L (reference range 269-641 nmol/L) independently predicts septic shock mortality. METHODS: A prospective observational study in patients with septic shock. Patients were categorized into 2 groups: mean plasma CBG concentrations <200 nmol/L and ≥200 nmol/L (day 1/2), with additional categorization by nadir CBG. Primary outcome was intensive care unit (ICU) mortality. Secondary outcomes were 28- and 90-day mortality, norepinephrine requirements, renal replacement therapy, and clinician-instituted hydrocortisone. RESULTS: 135 patients were included. Mortality rates in ICU were higher in the CBG < 200 nmol/L vs the CBG ≥ 200 nmol/L group: 32.4% vs 13.9% [odds ratio (OR) 2.97 (95% CI 1.19, 7.41); P = 0.02] with 28-day mortality OR 2.25 (95% CI 0.99, 5.11) and 90-day mortality OR 2.21 (95% CI 0.99, 4.91). Multivariate analysis revealed 4 factors independently associated with ICU mortality: CBG < 200 nmol/L (adjusted OR 3.23, 95% CI 1.06, 9.88), Acute Physiology and Chronic Health Evaluation II > 25 (adjusted OR 3.58, 95% CI 1.20, 10.68), Sequential Organ Failure Assessment (SOFA) liver score (adjusted OR 1.98, 95% CI 1.04, 3.72), and renal replacement therapy (adjusted OR 6.59, 95% CI 2.17, 20.01). Nadir CBG levels were associated with higher SOFA cardiovascular scores and norepinephrine total dose (µg; P < 0.01) and duration (days; P < 0.01). Plasma cortisol concentrations and hydrocortisone administration did not relate to ICU mortality. CONCLUSION: Septic shock patients with CBG < 200 nmol/L had higher norepinephrine requirements and 3.2-fold higher ICU mortality. CBG concentration was the only directly reversible independent mortality risk factor.