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2013 ; 368
(16
): 1477-88
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Reduced cortisol metabolism during critical illness
#MMPMID23506003
Boonen E
; Vervenne H
; Meersseman P
; Andrew R
; Mortier L
; Declercq PE
; Vanwijngaerden YM
; Spriet I
; Wouters PJ
; Vander Perre S
; Langouche L
; Vanhorebeek I
; Walker BR
; Van den Berghe G
N Engl J Med
2013[Apr]; 368
(16
): 1477-88
PMID23506003
show ga
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.).
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