Reduced Cortisol Metabolism During Critical Illness

Study Questions:

What is the contribution of reduced cortisol metabolism to sustained hypercortisolemia during critical illness?


Five biochemical aspects of cortisol metabolism were tested in 158 patients in the intensive care unit and 64 demographically matched controls. The following were measured: 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; urinary cortisol metabolites; and levels of messenger RNA (mRNA) and protein in liver and adipose tissue (to assess major cortisol-metabolizing enzymes). Biopsy samples (when collected) were obtained on autopsy.


Cortisol production was 83% higher in the critically ill patients (p = 0.02). In the presence of elevated cortisol levels, critically ill patients had lower corticotropin levels than did their controls (p < 0.001), and levels of cortisol did not correlate with corticotropin levels. There was a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of 100 mg in the patients (p ≤ 0.03 for both comparisons). Urinary steroid ratios, tracer kinetics, and assessment of liver-biopsy samples suggested reduced inactivation of cortisol in the liver and kidney (p ≤ 0.004 for all comparisons).


The authors concluded that critical illness is associated with suppressed expression and activity of cortisol-metabolizing enzymes, which contributes to hypercortisolemia.


The results from this study indicate that hypercortisolemia and corticotropin suppression may be related to not only an increase in cortisol production, but also reduced inactivation of cortisol in the liver and kidney. Study limitations aside, there are major clinical implications to these findings. These data suggest the limitations of a low cortisol response to corticotropin stimulation in diagnosing adrenal failure and call into question the practice of ‘stress doses’ of corticosteroids in critically ill patients. Going forward, treatment of adrenal insufficiency in the intensive care setting will probably need to account for more than augmentation of circulating levels.

Keywords: Deuterium, Liver, Critical Illness, RNA, Messenger

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