Reduced Cortisol Metabolism during Critical Illness
Open accessAbstract
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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During protracted critical illness, reduced metabolism and clearance contribute to hypercortisolaemia.
“During protracted critical illness, reduced metabolism and clearance contribute to hypercortisolaemia [11].”
From Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency (2020) · cites this paper as [11]
The plasma elimination half time of exogenously administered hydrocortisone is approximately 90 min, but may be shorter in patients taking inducers of liver enzyme CYP3A4 or suffering from hyperthyroidism, and longer in critically ill patients.
“The plasma elimination half time of exogenously administered hydrocortisone is approximately 90 min, but may be shorter in patients taking inducers of liver enzyme CYP3A4 [4] or suffering from hyperthyroidism, and longer in critically ill patients [11].”
From Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency (2020) · cites this paper as [11]
Reduced cortisol clearance during critical illness may affect the requirements of hydrocortisone in patients with adrenal insufficiency and should be taken into consideration when interpreting the findings.
“The previously reported reduced cortisol clearance during critical illness (30) may affect the requirements of hydrocortisone in patients with adrenal insufficiency and should be taken into consideration when interpreting our findings.”
From Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery (2020) · cites this paper as [30]
It is unlikely that hydrocortisone doses higher than 200 mg per 24 hours would be required to cover patients with adrenal insufficiency in sepsis, as critical illness results in a decrease in cortisol inactivation.
“Though we observed the highest serum cortisol concentrations in sepsis, it is unlikely that hydrocortisone doses higher than 200 mg per 24 hours would be required to cover patients with adrenal insufficiency in that situation, as critical illness results in a decrease in cortisol inactivation (30).”
From Prevention of adrenal crisis: cortisol responses to major stress compared to stress dose hydrocortisone delivery (2020) · cites this paper as [30]
Inflammation decreases the expression and activity of hepatic 5-reductases and probably those in other tissues.
“The expression and activity of 5-reductases within the liver and probably other tissues is decreased in response to inflammation [14].”
Cortisol production rates in critically ill patients are either unchanged or only slightly higher than in matched ICU control subjects.
“Cortisol production rates in critically ill patients were recently shown to be either unaltered or only slightly increased compared with matched control subjects tested in an intensive care unit (ICU) environment [14,15].”
Decreased ACTH levels are observed during the first week of ICU stay.
“Decreased ACTH levels are observed during the first week of ICU stay [14,15].”
The half-life of cortisol is dramatically increased during severe sepsis and other critical illnesses.
“Several studies have also demonstrated that the half-life of cortisol is dramatically increased during severe sepsis and other critical illnesses [14,15].”
Clinical studies find ACTH levels significantly lower in critically ill septic patients than in healthy volunteers.
“Compared with healthy volunteers, clinical studies have found ACTH levels to be significantly lower in critically ill septic patients [14,64,65].”
Feedback inhibition by elevated circulating free cortisol, driven by ACTH-independent mechanisms and suppressed cortisol breakdown, can suppress ACTH.
“In addition, feedback inhibition exerted by elevated circulating free cortisol, driven by ACTH-independent mechanisms and suppressed cortisol breakdown, can suppress ACTH [14,15,59].”
Some evidence suggests that cortisol production rate is somewhat increased in critically ill patients with systemic inflammatory response syndrome.
“There is some evidence that cortisol production rate is somewhat increased in critically ill patients with systemic inflammatory response syndrome [14].”
In vivo and ex vivo experiments show that the expression and activity of glucocorticoid-inactivating 5-reductase enzymes are decreased.
“Experiments involving a range of in vivo and ex vivo techniques showed that the expression and activity of the glucocorticoid-inactivating 5-reductase enzymes are decreased [14].”
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“Given The plasma elimination half time of exogenously administered hydrocortisone is approximately 90 min, but may be shorter in patients taking inducers of liver enzyme CYP3A4 [4] or suffering from hyperthyroidism, and longer in critically ill patients [11].”
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Self-citationClinical and Technical Aspects in Free Cortisol Measurement
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Endocrine aspects of ACE2 regulation: RAAS, steroid hormones and SARS-CoV-2
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Critical Illness–induced Corticosteroid Insufficiency: What It Is Not and What It Could Be
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The Hypothalamic–Pituitary–Adrenal Axis and Anesthetics: A Review
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Relative Adrenal Insufficiency in Patients with Cirrhosis: A Systematic Review and Meta-Analysis
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- Authors
- Boonen, E., Vervenne, H., Meersseman, P., Andrew, R., Mortier, L., Declercq, P. E., Vanwijngaerden, Y.-M., Spriet, I., Wouters, P. J., Vander Perre, S., Langouche, L., Vanhorebeek, I., Walker, B. R., & Van den Berghe, G.
- Affiliations
- KU Leuven (BE)
- University of Edinburgh (GB)
- Jessa Hospital (BE)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2013-04-18
- Volume
- 368
- Issue
- 16
- Pages
- 1477-1488
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC4413428
- OpenAlex
- W2100018795
- Semantic Scholar
- 7f3c17a02a9bca722a1820d94cd4def2c6c9328d
- Cited by
- 477
- References
- 44
- Citations by year
- 2026: 17 · 2025: 24 · 2024: 28 · 2023: 19 · 2022: 40 · 2021: 39 · 2020: 40 · 2019: 35 · 2018: 38 · 2017: 45 · 2016: 41 · 2015: 36 · 2014: 58 · 2013: 15
- FWCI
- 39.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (090937)
- British Heart Foundation (RG/11/4/28734)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- cortisol metabolism, critical illness, hypercortisolism, hypothalamic-pituitary-adrenal axis, cortisol clearance, cortisol, urinary steroid metabolites, intensive care unit patients
- MeSH terms
- Adrenocorticotropic Hormone, Aged, Cushing Syndrome, Female, Humans, Hydrocortisone, Intensive Care Units, Male, Middle Aged, RNA, Messenger, Case-Control Studies, Critical Illness, 11-beta-Hydroxysteroid Dehydrogenases
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