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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 [11].”
From Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency (2020) · cites this paper as [11]
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In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“The expression and activity of 5-reductases within the liver and probably other tissues is decreased in response to inflammation [14].”
In the citing paper
“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].”
In the citing paper
“Decreased ACTH levels are observed during the first week of ICU stay [14,15].”
In the citing paper
“Several studies have also demonstrated that the half-life of cortisol is dramatically increased during severe sepsis and other critical illnesses [14,15].”
In the citing paper
“Compared with healthy volunteers, clinical studies have found ACTH levels to be significantly lower in critically ill septic patients [14,64,65].”
In the citing paper
“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].”
In the citing paper
“There is some evidence that cortisol production rate is somewhat increased in critically ill patients with systemic inflammatory response syndrome [14].”
In the citing paper
“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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Metadata
- 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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