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Published on: June 15, 2019
Depletion of high-affinity corticosteroid-binding globulin corresponds to illness severity in sepsis and septic
M A Nenke1,2, W Rankin3, M J Chapman4
1Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia.
Insights
In sepsis, high-affinity corticosteroid-binding globulin (haCBG) levels decrease significantly with illness severity. This reduction in haCBG may impair cortisol delivery to inflammatory sites, potentially worsening sepsis outcomes.
Area of Science:
- Endocrinology
- Immunology
- Critical Care Medicine
Background:
- Corticosteroid-binding globulin (CBG) exists in high-affinity (haCBG) and low-affinity (laCBG) conformations.
- Neutrophil elastase cleaves CBG, converting haCBG to laCBG, which has reduced cortisol-binding affinity.
- In vitro studies suggest CBG cleavage facilitates targeted cortisol delivery to inflammation.
Purpose of the Study:
- To investigate in vivo whether CBG cleavage alters circulating haCBG and laCBG levels in sepsis patients.
- To correlate CBG conformation levels with sepsis severity.
Main Methods:
- Prospective, observational cohort study in an adult Intensive Care Unit.
- Recruited 33 patients with sepsis or septic shock, categorized by illness severity.
- Measured plasma haCBG, laCBG, total cortisol, and free cortisol using in-house assays.
Main Results:
- Plasma total CBG and haCBG levels significantly decreased with increasing sepsis severity (P < 0.0001).
- Free and total cortisol levels showed a nonsignificant trend of increase with worsening illness severity.
- haCBG levels correlated better with illness severity than free or total cortisol.
Conclusions:
- Circulating haCBG concentrations are markedly reduced in vivo in patients with increasing sepsis and septic shock severity.
- Low haCBG levels in chronic inflammation may limit cortisol availability at inflammatory sites.
- This limitation could potentially perpetuate the inflammatory process in sepsis.
Objective:
Corticosteroid-binding globulin (CBG) is cleaved by neutrophil elastase converting the high-affinity (haCBG) conformation of CBG to a low-affinity (laCBG) conformation with a ninefold reduced cortisol-binding affinity. These in vitro data suggest that cortisol release by CBG cleavage results in the targeted delivery of cortisol to areas of inflammation. Our objective was to determine whether CBG cleavage alters circulating levels of haCBG and laCBG in vivo in proportion to sepsis severity.
Design:
Prospective, observational cohort study in an adult tertiary level Intensive Care Unit in Adelaide, Australia.
Patients:
Thirty-three patients with sepsis or septic shock grouped by illness severity [sepsis, septic shock survivors, septic shock nonsurvivors and other shock].
Measurements:
Plasma levels of haCBG and laCBG were assessed using a recently developed in-house assay in patients. Plasma total and free cortisol levels were also measured.
Results:
Plasma total CBG and haCBG levels fell significantly, in proportion to disease severity (P < 0·0001 for both). There was a nonsignificant increase in free and total cortisol as illness severity worsened (P = 0·19 and P = 0·39, respectively). Illness severity was better correlated with haCBG levels than either free or total cortisol levels.
Conclusions:
Increasing illness severity in sepsis and septic shock is associated with markedly reduced circulating haCBG concentrations in vivo. We propose that low levels of haCBG in chronic inflammation may limit the availability of cortisol to inflammatory sites, perpetuating the inflammatory process.
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