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Peer-reviewedCC BY 4.0Frontiers in Endocrinology

Routine blood-based immune signatures in endogenous Cushing’s syndrome: associations with cortisol excess and selected complication burden

  • Yunjia Cai1,2
  • Shuwen Tan1
  • Siyuan Liu1
  • Miao Wang3
  • Tiemin Liu2
  • Guixia Wang1
  1. 1Department of Endocrinology and Metabolism, The First Hospital of Jilin University
  2. 2State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University
  3. 3Department of Obstetrics and Gynecology, Jilin Province People’s Hospital
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Abstract

Background: Routine blood-based markers capture glucocorticoid-related immune-cell redistribution, but whether these measures are associated with complementary biochemical measures of cortisol excess and clinical complication burden in endogenous Cushing’s syndrome remains unclear.

Methods: We included 202 patients with endogenous Cushing’s syndrome. Seven routine blood-based immune markers were examined in relation to 24h urinary free cortisol (24h-UFC), midnight serum cortisol, and 8 a.m. serum cortisol. Selected immune markers were further evaluated in relation to clinical complications. An exploratory complication-domain burden score comprised four domains: electrolyte involvement, hypertension, diabetes, and fracture. An exploratory cortisol-related immune score (CRIS) combined neutrophil-to-lymphocyte ratio (NLR), eosinophil depletion, and low prognostic nutritional index (PNI).

Results: All seven immune markers were significantly associated with each of the three biochemical cortisol measures after adjustment for age, sex, and aetiology, with NLR and absolute eosinophil count (AEC) showing the strongest and most consistent associations. For 24h-UFC, the adjusted coefficients were 0.647 for log-NLR and −0.687 for log(AEC + 0.01) per 1 SD increase. In primary complication analyses, significant associations after false-discovery rate (FDR) correction were observed for hypokalaemia, hypophosphataemia, diabetes, and fracture; for example, log-NLR was associated with hypophosphataemia (OR 2.86, 95% CI 1.39–6.33), while low PNI was associated with fracture (OR 2.52, 95% CI 1.60–3.96). Each 1 SD increase in CRIS was associated with a higher complication-domain burden score (IRR 1.20, 95% CI 1.07–1.35; P = 0.001).

Conclusion: Routine blood-based immune markers were associated with complementary biochemical measures of cortisol excess and selected clinical complications in endogenous Cushing’s syndrome. Eosinophil depletion and increased NLR were consistently associated with all three cortisol measures, whereas associations with clinical complications varied by marker and outcome. CRIS provided an exploratory integrative summary of cortisol-related immune alterations and selected complication-domain burden but requires external validation.

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Cite

BibTeXRIS
BibTeX
@article{cai2026routine,
  title = {{Routine blood-based immune signatures in endogenous Cushing’s syndrome: associations with cortisol excess and selected complication burden}},
  author = {Yunjia Cai and Shuwen Tan and Siyuan Liu and Miao Wang and Tiemin Liu and Guixia Wang},
  journal = {Frontiers in Endocrinology},
  year = {2026},
  month = oct,
  doi = {10.3389/fendo.2026.1961986},
  url = {https://www.frontiersin.org/articles/10.3389/fendo.2026.1961986/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Routine blood-based immune signatures in endogenous Cushing’s syndrome: associations with cortisol excess and selected complication burden
AU  - Yunjia Cai
AU  - Shuwen Tan
AU  - Siyuan Liu
AU  - Miao Wang
AU  - Tiemin Liu
AU  - Guixia Wang
PY  - 2026
DA  - 2026/10/22
JO  - Frontiers in Endocrinology
DO  - 10.3389/fendo.2026.1961986
UR  - https://www.frontiersin.org/articles/10.3389/fendo.2026.1961986/full
AB  - Background: Routine blood-based markers capture glucocorticoid-related immune-cell redistribution, but whether these measures are associated with complementary biochemical measures of cortisol excess and clinical complication burden in endogenous Cushing’s syndrome remains unclear.  Methods: We included 202 patients with endogenous Cushing’s syndrome. Seven routine blood-based immune markers were examined in relation to 24h urinary free cortisol (24h-UFC), midnight serum cortisol, and 8 a.m. serum cortisol. Selected immune markers were further evaluated in relation to clinical complications. An exploratory complication-domain burden score comprised four domains: electrolyte involvement, hypertension, diabetes, and fracture. An exploratory cortisol-related immune score (CRIS) combined neutrophil-to-lymphocyte ratio (NLR), eosinophil depletion, and low prognostic nutritional index (PNI).  Results: All seven immune markers were significantly associated with each of the three biochemical cortisol measures after adjustment for age, sex, and aetiology, with NLR and absolute eosinophil count (AEC) showing the strongest and most consistent associations. For 24h-UFC, the adjusted coefficients were 0.647 for log-NLR and −0.687 for log(AEC + 0.01) per 1 SD increase. In primary complication analyses, significant associations after false-discovery rate (FDR) correction were observed for hypokalaemia, hypophosphataemia, diabetes, and fracture; for example, log-NLR was associated with hypophosphataemia (OR 2.86, 95% CI 1.39–6.33), while low PNI was associated with fracture (OR 2.52, 95% CI 1.60–3.96). Each 1 SD increase in CRIS was associated with a higher complication-domain burden score (IRR 1.20, 95% CI 1.07–1.35; P = 0.001).  Conclusion: Routine blood-based immune markers were associated with complementary biochemical measures of cortisol excess and selected clinical complications in endogenous Cushing’s syndrome. Eosinophil depletion and increased NLR were consistently associated with all three cortisol measures, whereas associations with clinical complications varied by marker and outcome. CRIS provided an exploratory integrative summary of cortisol-related immune alterations and selected complication-domain burden but requires external validation.
SN  - 1664-2392
ER  -