Reduced cortisol metabolism contributed to abnormal blood hormone levels

Issue: April 2013

Within the literature, reductions in cortisol are attributed to stress-induced activation of the hypothalamic–pituitary–adrenal axis and increased corticotropin-driven cortisol production. However, critically ill patients in the ICU with reduced cortisol breakdown tended to have abnormal blood cortisol levels, which researchers said could play a role in the diagnosis of adrenal failure and treatment options within this setting.

Perspective from Eliza B. Geer, MD

Eva Boonen, MD, of the department of intensive care medicine at KU Leuven in Leuven, Belgium, and colleagues conducted five clinical studies comparing 158 patients in the ICU with 64 matched controls.

According to data, the total and free circulating cortisol levels were found to be consistently greater among patients compared with controls. However, corticotropin levels were lower (P<.001), researchers wrote. Additionally, cortisol production was 83% higher among patients (P=.02), with a reduction of more than 50% in cortisol clearance during tracer infusion and after the administration of hydrocortisone 100 mg (P≤.03).

Researchers also reported an increase in plasma cortisol levels by a factor of 3.5 in patients when all factors were accounted for vs. controls (P<.0001).

Further data indicate a correlation between impaired cortisol clearance and a lower cortisol response to corticotropin stimulation, researchers wrote.

“These findings have clinical implications. The contribution of reduced cortisol breakdown to hypercortisolemia during critical illness changes our understanding of the stress response,” Boonen and colleagues wrote. “Reduced inactivation of cortisol may be important not only to increase circulating levels, but also to potentiate cortisol levels and activity within the vital tissues that express inactivating enzymes.”

In an accompanying editorial, Celso E. Gomez-Sanchez, MD, of the endocrine section of Montgomery VA Medical Center and University of Mississippi Medical Center, wrote that the study by Boonen and colleagues did not fully address the mechanism of cortisol hypersecretion.

“Study patients with systemic inflammatory response syndrome (SIRS) had increased adrenal cortisol production; those without SIRS had normal production,” Gomez-Sanchez wrote.

He concluded that multiple changes in cortisol homeostasis occur in critically ill patients, and alterations that contribute to adrenal failure were clarified within the study.

For more information:

Boonen E. N Engl J Med. 2013;doi:10.1056/NEJMoa1214969.

Gomez-Sanchez CE. N Engl J Med. 2013;doi:10.1056/NEJMe1302305.

Disclosure: The researchers report no relevant financial disclosures.

Perspective

Eliza B. Geer, MD

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.

Eliza B. Geer, MD

Assistant professor of medicine in endocrinology, diabetes and bone disease; neurosurgery

Mount Sinai School of Medicine

Disclosures: Geer reports no relevant financial disclosures.