Total and high‐affinity corticosteroid‐binding globulin depletion in septic shock is associated with mortality

Abstract

Low circulating haCBG concentrations are associated with mortality in septic shock. These results are consistent with an important physiological role for haCBG in cortisol tissue delivery in septic shock.

Pyrexia and acidosis act independently of neutrophil elastase reactive center loop cleavage to effect cortisol release from corticosteroid‐binding globulin

“…Our previous human studies have demonstrated that a lack of targeted delivery of natural cortisol and/or administered hydrocortisone to damaged tissue is related to deficient serum concentrations of CBG, which perpetuates organ failure and death in sepsis. 13,14 To further probe the action of CBG in the finely tuned delivery of cortisol and other steroids, we developed a novel ligand binding assay. The chosen SPR technology provided a reproducible and readily applicable, direct ligand binding assay to quantitate the bimolecular interaction between recombinant CBG and a library of 19 steroids.…”

“…Our previous research has revealed falling serum haCBG concentrations over time in proportion to septic shock severity and lower haCBG levels is associated with septic shock mortality. 13,14 In sepsis and septic shock with attendant multi-organ failure and hepatic dysfunction, protein glycosylation does not increase, thus it is unlikely that the reduction in 9G12 reactive CBG is due to an increase in CBG glycosylation of the RCL in these states. Furthermore, a loss in 9G12 reactive CBG correlates with rising free cortisol concentrations in sepsis and septic shock.…”

“…Systemically, we have shown that falling serum concentrations of haCBG correlate to increasing illness severity in sepsis/septic shock and with the risk of mortality due to dysregulated delivery of sterols. 13,14 In addition to this NE-mediated delivery mechanism cortisol is liberated from CBG by increased temperature and possibly also by acidemia, conditions typical of sepsis. 7,15 Hydrocortisone binding studies using glycosylated human CBG pooled from plasma revealed that the equilibrium binding constants (K D ) increased four-fold when the temperature was elevated from 37 to 42 C. 7,16 CBG: hydrocortisone binding affinity was not affected by pH but technical limitations were reported by the authors.…”

Demystifying adrenal dysfunction in severe illness

“…Depletion of high affinity corticosteroid binding globulin (CBG) has been proposed to be an important adverse mechanism in critical illness. 6 In the absence of intact CBG, the delivery of glucocorticoids to tissues might be severely impaired even in the presence of a high serum level of steroid.…”

“…The study also does not address whether other aspects of glucocorticoid signalling aside from serum cortisol levels might become dysfunctional in severe illness. Depletion of high affinity corticosteroid binding globulin (CBG) has been proposed to be an important adverse mechanism in critical illness . In the absence of intact CBG, the delivery of glucocorticoids to tissues might be severely impaired even in the presence of a high serum level of steroid.…”