title: Validation of a simple method of estimating plasma free cortisol: role of cortisol binding to albumin.
abstract: OBJECTIVE
  To develop, optimize, and validate a generalized mass action, equilibrium solution that incorporates measured concentrations of albumin as well as cortisol binding globulin (CBG) to estimate free cortisol.
  
  
  METHODS
  Free cortisol was estimated by Coolens method or by cubic equilibrium equation and compared to measured free cortisol, determined by ultrafiltration method, in subjects with septic shock (n=45), sepsis (n=19), and healthy controls (n=10) at 0, 30, and 60 min following administration of cosyntropin (250 mcg). The data set also included repeat testing in 30 subjects following recovery from sepsis/septic shock. The equilibrium dissociation constant for cortisol binding to albumin (K(A)) was optimized by non-linear regression. The cubic equilibrium solution was also used to model the influence of cortisol, CBG, and albumin concentration on free cortisol.
  
  
  RESULTS
  Compared to measured free cortisol, the cubic solution, using an optimized K(A) of 137,800 nM, was less biased than Coolens solution, with mean percent error of -23.0% vs. -41.1% (paired t test, P<0.001). Standard deviation values were also significantly lower (Wilks' test, P<0.001) for the cubic solution (SD 35.8% vs. 40.8% for cubic vs. Coolens, respectively). Modeling studies using the cubic solution suggest an interaction effect by which low concentrations of CBG and albumin contribute to a greater increase in free cortisol than the sum of their independent effects.
  
  
  CONCLUSIONS
  Mass action solutions that incorporate the measured concentration of albumin as well as CBG provide a reasonably accurate estimate of free cortisol that generalizes to conditions of health as well as a setting of hypercortisolism and low CBG and albumin concentrations associated with septic shock. Modeling studies emphasize the significant contribution of albumin deficiency and albumin-bound cortisol under conditions of CBG-deficiency, and identify a synergistic effect by which combined CBG and albumin deficiency contribute to elevation of free cortisol in septic shock.
authors.affiliation: Medical Service, New Mexico VA Healthcare System, Albuquerque, NM 87108, USA. rdorin@salud.unm.edu
authors.forename: Richard I
authors.initials: RI
authors.lastname: Dorin
authors.forename: Hemanth K
authors.initials: HK
authors.lastname: Pai
authors.forename: Jui T
authors.initials: JT
authors.lastname: Ho
authors.forename: John G
authors.initials: JG
authors.lastname: Lewis
authors.forename: David J
authors.initials: DJ
authors.lastname: Torpy
authors.forename: Frank K
authors.initials: FK
authors.lastname: Urban
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Qualls
mesh_terms: D002352:Carrier Proteins / Q000032:analysis* / Q000097:blood; D006801:Humans; D006854:Hydrocortisone / Q000097:blood*; D008432:Mathematical Computing; D011485:Protein Binding; D018805:Sepsis / Q000097:blood / Q000378:metabolism; D012709:Serum Albumin / Q000032:analysis*; D012772:Shock, Septic / Q000097:blood / Q000378:metabolism; D014462:Ultrafiltration
chemical_list: D002352:Carrier Proteins; D012709:Serum Albumin; C027091:cortisol binding globulin; D006854:Hydrocortisone