Background: Corticosteroid-binding globulin (CBG) regulates the delivery of anti-inflammatory cortisol to tissues. High-affinity CBG (haCBG) is cleaved by the serine proteinase neutrophil elastase (NE) at sites of inflammation, resulting in permanent transition to low cortisol-binding affinity form (laCBG), releasing free cortisol. Alpha-1 antitrypsin (AAT) is the major circulating inhibitor of NE. Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant condition that predisposes patients to early-onset emphysema and cirrhosis due to increased proteolytic destruction from the inherent proteinase:antiproteinase imbalance.
Hypothesis: That deficiency of AAT should lead to increased NE activity and therefore increased CBG cleavage in vivo, with decreased absolute and relative levels of the native haCBG and increased laCBG, with important implications for the pathogenesis and treatment of AATD.
Methods: We performed a prospective observational study of 10 patients with stable AATD and 28 controls. Plasma total CBG, haCBG and laCBG forms were measured by in-house parallel monoclonal ELISAs. AAT, total and free cortisol levels were also measured.
Results: Mean ± SEM circulating levels of total CBG were similar among AATD patients and controls (512 ± 46 and 498 ± 15 nmol/L; P=0.8), but haCBG was significantly higher (353 ± 36 and 264 ± 8 nmol/L; P<0.005), and laCBG lower (159 ± 19 and 225 ± 11 nmol/L; P=0.016) in the AATD group. The ratio of haCBG:totalCBG was significantly higher in AATD (69 ± 3% and 54 ± 1.3%; P=0.0001). There was a significant negative correlation between haCBG:totalCBG and AAT levels (P<0.05, R=0.67), but no correlation between AAT and cortisol indices.
Conclusions: Despite a lack of AAT and excess uninhibited NE, CBG cleavage is paradoxically reduced in AATD under basal conditions with increased absolute and relative levels of haCBG compared with controls. The pathogenic implications for cortisol delivery under conditions of acute or subacute infection require further study.