Free Cortisol Index Is Better Than Serum Total Cortisol in Determining Hypothalamic-Pituitary-Adrenal Status in Patients Undergoing Surgery
Abstract
Serum total cortisol has traditionally been used for the interpretation of tests of the hypothalamic-pituitary-adrenal axis. Approximately 80% of total cortisol is bound to cortisol-binding globulin (CBG), and variation in CBG significantly affects serum total cortisol levels. Reliable assessment of hypothalamic-pituitary-adrenal axis reserve is difficult in severely ill patients, because CBG falls substantially during the acute phase response. The free cortisol index (FCI), defined as the ratio of total cortisol/CBG, correlates well with serum free cortisol. We evaluated the FCI in the context of severe stress and the acute phase response by measuring total cortisol and CBG pre- and postoperatively in 31 patients undergoing major elective surgery. Serum total cortisol increased by 55% from 453 +/- 35.2 (mean +/- SEM) nmol/liter (range, 88-882) to 700 +/- 47.2 (range, 294-1631) nmol/liter. Serum CBG decreased by 30% from 45 +/- 1.7 (range, 26.6-64.1) to 31.4 +/- 1.62 (range, 16.1-51.9) mg/liter, but FCI increased by 130% from 10 +/- 0.8 (range, 2-18) to 23 +/- 1.7 (range, 13-58) nmol/mg. In seven patients (23%), postoperative serum total cortisol was less than 500 nmol/liter, but their postoperative CBG levels were significantly lower than levels in the rest of the group (P < 0.01). However, there was no difference in the FCI between this subgroup and the rest of the group. This study demonstrates the importance of CBG measurement and the calculation of FCI for the interpretation of serum total cortisol in situations where CBG changes significantly.
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Free cortisol correlates better with HPA axis activation/reserve than total cortisol; total cortisol alone could misdiagnose HPA insufficiency in up to 23% of critically ill surgical patients.
“For instance, activation and reserve capacity of the hypothalamic–pituitary–adrenal (HPA) axis in critically ill patients undergoing surgery was found to correlate better with serum free than total cortisol concentrations. The use of serum total cortisol alone could lead to a misdiagnosis of HPA axis insufficiency in up to 23% of these patients [241, 242].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [242]
The Discussion (page not supplied) says that 23% of the patients would have been misdiagnosed with HPA-axis insufficiency using total-cortisol criteria, and that the free cortisol index better evaluates reserve when binding proteins change. But the study examined patients undergoing major elective surgery, not a cohort described as critically ill, and measured the free cortisol index rather than directly measuring serum free cortisol. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPatients with nephrotic syndrome, liver disease, immediate postoperative period, or requiring intensive care may have lower CBG and albumin and hence lower cortisol measurements.
“Patients with diseases such as nephrotic syndrome (43) and liver disease (50) as well as those who are in the immediate postoperative period (51) or who require intensive care (52) may have lower CBG and albumin and hence, lower cortisol measurements.”
From Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline (2016) · cites this paper as [51]
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“FCI [11, 12]”
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“At the same time the importance of measuring free, not total, cortisol in ACTH stimulation tests is also gaining recognition (10, 26, 27).”
BackgroundNon-enzymatic electrochemical determination of salivary cortisol using ZnO-graphene nanocomposites
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“Interpretation of plasma total cortisol concentrations, in situations where CBG changes significantly, does not address the free cortisol fraction and thus may not provide a true representation of its biological impact (le Roux et al. 2003).”
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“Free cortisol, which is technically demanding to measure, mirrors better cortisol availability [43] and may be important in understanding the lack of changes in GCR isoforms over time and the changes in downstream targets in PBMCs and PMNs. Neverthe-less, in critical illness, tissue cortisol levels…”
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Is drug-induced hepatitis related to the severity of tuberculous meningitis?
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- Authors
- le Roux, C. W., Chapman, G. A., Kong, W. M., Dhillo, W. S., Jones, J., & Alaghband-Zadeh, J.
- Affiliations
- Bradford Royal Infirmary (GB)
- Hammersmith Hospital (GB)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2003-05
- Volume
- 88
- Issue
- 5
- Pages
- 2045-2048
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2023342988
- Cited by
- 146
- References
- 19
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 2 · 2023: 2 · 2022: 3 · 2021: 7 · 2020: 3 · 2019: 7 · 2018: 6 · 2017: 7 · 2016: 4 · 2015: 7 · 2014: 6 · 2013: 6 · 2012: 5
- FWCI
- 3.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- 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 › Hyperglycemia and glycemic control in critically ill and hospitalized patients
- Keywords
- corticosteroid-binding globulin, hypothalamic-pituitary-adrenal axis, acute phase response, surgical stress, elective major surgery, postoperative cortisol, adrenal reserve
- MeSH terms
- Adrenal Glands, Adult, Carrier Proteins, Female, Humans, Hydrocortisone, Hypothalamus, Male, Middle Aged, Pituitary Gland, Protein Binding, Reference Values, Sensitivity and Specificity, Stress, Physiological, Surgical Procedures, Operative, Time Factors
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