title: Reduced cortisol metabolism during critical illness.
abstract: BACKGROUND
  Critical illness is often accompanied by hypercortisolemia, which has been attributed to stress-induced activation of the hypothalamic-pituitary-adrenal axis. However, low corticotropin levels have also been reported in critically ill patients, which may be due to reduced cortisol metabolism.
  
  
  METHODS
  In a total of 158 patients in the intensive care unit and 64 matched controls, we tested five aspects of cortisol metabolism: daily levels of corticotropin and cortisol; plasma cortisol clearance, metabolism, and production during infusion of deuterium-labeled steroid hormones as tracers; plasma clearance of 100 mg of hydrocortisone; levels of urinary cortisol metabolites; and levels of messenger RNA and protein in liver and adipose tissue, to assess major cortisol-metabolizing enzymes.
  
  
  RESULTS
  Total and free circulating cortisol levels were consistently higher in the patients than in controls, whereas corticotropin levels were lower (P<0.001 for both comparisons). Cortisol production was 83% higher in the patients (P=0.02). There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg of hydrocortisone in the patients (P≤0.03 for both comparisons). All these factors accounted for an increase by a factor of 3.5 in plasma cortisol levels in the patients, as compared with controls (P<0.001). Impaired cortisol clearance also correlated with a lower cortisol response to corticotropin stimulation. Reduced cortisol metabolism was associated with reduced inactivation of cortisol in the liver and kidney, as suggested by urinary steroid ratios, tracer kinetics, and assessment of liver-biopsy samples (P≤0.004 for all comparisons).
  
  
  CONCLUSIONS
  During critical illness, reduced cortisol breakdown, related to suppressed expression and activity of cortisol-metabolizing enzymes, contributed to hypercortisolemia and hence corticotropin suppression. The diagnostic and therapeutic implications for critically ill patients are unknown. (Funded by the Belgian Fund for Scientific Research and others; ClinicalTrials.gov numbers, NCT00512122 and NCT00115479; and Current Controlled Trials numbers, ISRCTN49433936, ISRCTN49306926, and ISRCTN08083905.).
authors.affiliation: Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Eva
authors.initials: E
authors.lastname: Boonen
authors.forename: Hilke
authors.initials: H
authors.lastname: Vervenne
authors.forename: Philippe
authors.initials: P
authors.lastname: Meersseman
authors.forename: Ruth
authors.initials: R
authors.lastname: Andrew
authors.forename: Leen
authors.initials: L
authors.lastname: Mortier
authors.forename: Peter E
authors.initials: PE
authors.lastname: Declercq
authors.forename: Yoo-Mee
authors.initials: YM
authors.lastname: Vanwijngaerden
authors.forename: Isabel
authors.initials: I
authors.lastname: Spriet
authors.forename: Pieter J
authors.initials: PJ
authors.lastname: Wouters
authors.forename: Sarah
authors.initials: S
authors.lastname: Vander Perre
authors.forename: Lies
authors.initials: L
authors.lastname: Langouche
authors.forename: Ilse
authors.initials: I
authors.lastname: Vanhorebeek
authors.forename: Brian R
authors.initials: BR
authors.lastname: Walker
authors.forename: Greet
authors.initials: G
authors.lastname: Van den Berghe
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D000368:Aged; D016022:Case-Control Studies; D016638:Critical Illness; D003480:Cushing Syndrome; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism*; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D000324:Adrenocorticotropic Hormone; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone