Reduced cortisol metabolism contributed to abnormal blood hormone levels

Physicians are handicapped when it comes to diagnosing relative (or partial) adrenal insufficiency in many settings, including the ICU setting, by lack of available and accurate diagnostic tests. Critically ill patients are particularly challenging because baseline and stimulated cortisol cut offs are higher due to severe stress, but appropriate cut offs are controversial, and the added effect of systemic inflammation, ICU medications, and decreased cortisol binding protein, among other factors, add to the confusion about which patients require stress dose glucocorticoids. This study by Boonen et al. adds valuable information on the physiology of the HPA axis during critical illness. They show that the axis is not up-regulated from the top down, but rather by alterations in cortisol metabolism and clearance. Through a number of studies looking at cortisol production, clearance, and activity of cortisol metabolizing enzymes, they show that critically ill patients have increased cortisol production, in addition to impaired clearance, which results in elevated circulating cortisol despite reduced corticotropin concentrations. Interestingly, cortisol production, but also clearance, seems to correlate with serum cortisol response to 250 mcg corticotropin stimulation. The significance of this is unclear, since as shown here, ICU patients have increased production but decreased clearance, and the standard corticotropin stimulation test has obvious limitations in diagnosing adrenal insufficiency. This study’s data also suggest that currently prescribed ICU “stress” dose steroids may be too high, although most physicians would rather err on giving too much rather than too little in this setting. 

The results of this important and thorough study shed light on the physiology of cortisol metabolism in critically ill patients, and thus these results have implications for diagnosis and treatment of adrenal insufficiency in the ICU setting, as well as understanding HPA axis regulators in other settings. Whether cortisol metabolism is reduced as a compensatory mechanism during severe illness, i.e. the body’s “appropriate” response to stress, or whether it reflects dysfunctional cortisol regulation remains unknown. Similarly, whether elevated serum cortisol concentrations, here due to enhanced production and impaired clearance, reflect HPA axis sufficiency (therefore suggesting that exogenous glucocorticoids are not needed) or whether these patients may still benefit from exogenous stress glucocorticoids is not known. Finally, clinical outcomes of impaired cortisol metabolism are not known, and may be difficult to ascertain in this setting of critical illness.